Compounds, compositions and methods

ABSTRACT

The present invention provides methods and pharmaceutical compositions for inhibiting expressions of HIF and HIF regulated genes, inhibiting angiogenesis, inducing cell cycle arrest in tumor cells, and treating cell proliferating diseases or conditions.

CLAIM OF PRIORITY

The priority of provisional applications Ser. No. 60/484,158, filed Jun.30, 2003, Ser. No. 60/484,191, filed Jun. 30, 2003, Ser. No. 60/534,001,filed Dec. 31, 2003 and Ser. No. 60/533,985, filed Dec. 31, 2003 ishereby claimed pursuant to 35 USC 119(e). The disclosures of theseapplications are incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

The present invention relates to methods and pharmaceutical compositionsfor inhibiting tumor growth by arresting the cell cycle or bysuppressing HIF-regulated gene expression, inhibiting angiogenesis intumor cells or tissues, and for treating HIF mediated disorders orconditions.

BACKGROUND OF THE INVENTION

Hypoxia, a reduction in tissue oxygen levels below physiologic levels,commonly develops within solid tumors because tumor cell proliferationis greater than the rate of blood vessel formation. Thus, the increasein tumor mass results in aberrant vasculature formation, whichcompromises the blood supply (Hockel et al., J Natl Cancer Inst 200193:266-276). Tumor hypoxia is one stimulus that leads to the increasedexpression of vascular endothelial growth factor (VEGF) and stimulatesangiogenesis, which is essential for meeting the metabolic requirementsof tumor growth (Dachs et al., Eur J Cancer 2000 36:1649-1660). Inaddition, hypoxia contributes to tumor progression to a more malignantphenotype because cells surviving under hypoxic conditions often becomeresistant to radiotherapy and chemotherapy (Brown, J. M. Cancer Res 199959:5863-5870). Thus, factors that regulate the hypoxic events may begood targets for anticancer therapy.

One such target is hypoxia-inducible factor 1 (HIF-1). HIF-1 is a keytranscription factor that regulates the blood supply through theexpression of vascular endothelial growth factor (VEGF) (Forsythe etal., Mol Cell Biol 1996 16:4604-4613). The biologic activity of HIF-1, aheterodimer composed of HIF-1α and HIF-1β (Wang et al., J Biol Chem 1995270:1230-1237), depends on the amount of HIF-1α, which is tightlyregulated by oxygen tension. Under normoxic conditions, HIF-1α proteinis unstable. The instability is mainly regulated by the binding to thevon Hippel-Lindau tumor suppressor protein (pVHL) (Maxwell et al.,Nature 1999 399:271-275). This binding occurs after the hydroxylation ofthe two HIF-1α proline residues by HIF-prolyl hyroxylases (Jaakkola etal., Science 2001 292:468-472; Ivan et al., Science 2001 292:464-468;Masson et al., EMBO J. 2001 20:5197-5206). The von Hippel-Lindau proteinis one of the components of the multiprotein ubiquitin-E3-ligasecomplex, which mediates the ubiquitylation of HIF-1α, targeting it forproteasomal proteolysis (Huang et al., Proc Natl Acad Sci USA 199895:7987-7992). However, under hypoxic conditions, proline hydroxylationis inhibited, binding between HIF-1 and the von Hippel-Lindau protein iseliminated and HIF-1α becomes stable.

HIF-2α (also known as endothelial PAS protein-1 or MOP2) is anothermember in HIF family. It was found by homology searches in the gene bankand by cloning experiments. HIF-2α is highly similar to HIF-1α inprotein structure, but exhibits restricted tissue-specific expression.HIF-2α is also tightly regulated by oxygen tension and its complex withHIF-1β appears to be directly involved in hypoxic gene regulation, as isHIF-1α. Since HIF-2α is expressed in a number of cancer cell lines andinvolved in hypoxic gene regulation, HIF-2α is also suggested to beassociated with tumor promotion, but may not contribute to the growth ofmost tumors. In breast cancer cell lines that express both HIF-1α andHIF-2α, HIF-1α rather than HIF-2α appears to predominantly contribute tothe transcriptional response to hypoxia. However, HIF-2α may take overthe role of HIF-1α in tumors that express only HIF-2α. Indeed, in vonHippel-Lindau (VHL)-defective 786-O renal cell carcinoma cells, thetranscriptional response to hypoxia depended on expression levels ofHIF-2α. Moreover, the ectopic expression of HIF-2α led to enhancedgrowth of 786-0 tumors grafted in nude mice. Therefore, HIF-2α is also agood target for cancer treatment. See Semenza, G. L., Nature Reviews,Cancer, Vol. 3, (2003), pp. 70-81.

As used herein, the term HIF means the combined effect of or totalproteins of HIF-1 plus HIF-2. In addition the term HIF-1 means thecombined effect of or total proteins of HIF-1α plus HIF-1β. The termHIF-2 means the combined effect of or total proteins of HIF-2α plusHIF-2β.

While searching for anticancer agents that inhibit HIF-1 activity, weidentified a novel pharmacologic action of YC-1 and novel analogsthereof. YC-1, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole, has beenknown to inhibit platelet aggregation and vascular contraction byactivating soluble guanylyl cyclase, and was originally developed as apotential therapeutic agent for circulation disorders (Teng et al., EurJ Pharmacol 1997 320:161-166; Galle et al., Br J Pharmacol 1999127:195-203). Recently, we have found two novel biological actions ofYC-1 and novel analogs thereof; one is the inhibitory effect on eitherHIF-1 or HIF-2 activity, and the other is the anti-proliferative effecton cancer cells by arresting the cell cycle and leading to cellapoptosis.

The inhibitory effects of compounds of the invention on the expressionof HIF-1α and on the induction of VEGF, aldolase A, and enolase I incancer cells cultured under hypoxic conditions are also exhibited invivo, treatment by halting the growth of xenografted tumors originatingfrom human cancers, such as hepatoma, stomach carcinoma, renalcarcinoma, cervical carcinoma, neuroblastoma, and prostate carcinomacells. Tumors from mice treated with the compounds showed fewer bloodvessels and reduced expression of HIF-1α protein and HIF-1-regulatedgenes than tumors from vehicle-treated mice. These results support thatthe compounds are inhibitors of HIF-1 and HIF-2, and halt tumor growthby blocking tumor angiogenesis and tumor adaptation to hypoxia. Thecompounds are also useful against tumors that overexpress HIF proteins.

The eukaryotic cell cycle is divided into four stages: G1, S, G2, and M.G1 is the gap phase during which cells prepare for the process of DNAreplication. During this phase, cells integrate mitogenic andgrowth-inhibitory signals and make the decision to proceed, pause, orexit cell cycle. The S Phase is defined as the stage in which DNAsynthesis occurs. G2 is the second gap phase during which the cellprepares for the process of division. The M phase is defined as thestage in which the replicated chromosomes are segregated into separatenuclei and other cellular components are divided to make two daughtercells. In addition to G1, S, G2, and M, G0 is defined as the cell stagein which cells exit cell cycle and become quiescent. Cells have evolvedsignaling pathways to coordinate cell cycle transitions and ensurefaithful replication of the genome before cell division. Cell cycleprogression is stimulated by protein kinase complexes, each of whichconsists of a cyclin and a cyclin-dependent kinase (CDK). The CDK's areexpressed constitutively through cell cycle, whereas cyclin levels arerestricted by transcriptional regulation of the cyclin genes and byubiquitin-mediated degradation. The CDK activation requires the bindingof a cyclin partner in addition to site-specific phosphorylation. Tocarry on error-free cell cycle, eukaryotic cells have developed controlmechanisms that restrain cell cycle transitions in response to stress.These regulatory pathways are termed cell cycle checkpoints, which canbe divided into three points, i.e., G1-S, G2, and M phase checkpoint.Cells can arrest transiently at cell cycle checkpoints to allow for therepair of cellular damage. Alternatively, when the cell cycle arrest isdue to irreparable damage, checkpoint signaling activates pathways thatlead to apoptosis.

In most proliferative disorders, such as benign/malignant tumors,various visceral hyperplasia, vascular wall thickening due to smoothmuscle cell proliferation, psoriasis and proliferative retinal diseases,limitless cell proliferation is the most important manifestation.Basically, these disorders are caused by cell cycle dysregulation.Several genes encoding regulatory proteins that govern cell cycle aretargets for genetic and epigenetic alterations that underlie the genesisof the proliferative disorders. The best characterized of these genesare D-type cyclins. Amplification of the cyclin D genes occurs in asubset of breast, esophageal, bladder, lung, and squamous cellcarcinomas. In addition, cyclin D proteins are over-expressed in someprimary tumors and other proliferative disorders. In addition, thecatalytic partners of D-type cyclins cdk4 and cdk6 are over-expressedand hyper-activated in some tumors and tumor cell lines. Alterations inother cell cycle regulators have also been implicated in human cancer.Cyclin E has been found to be amplifed, overexpressed, or both in somebreast, colon carcinomas, and leukemias. A single instance in whichcyclin A was altered in a human hepatoma has been reported. Besidesthese cell cycle regulators, the genetic alterations of the checkpointregulators that induce cell cycle arrest are also associated with thegenesis of the proliferative disorders.

The p53 gene, whose product plays a key role in checkpoint regulation ofcell cycle, is the most frequently mutated gene in human cancer. Thestabilization of p53 in response to DNA damage results in enhancedexpression of p21, which in turn stops cell cycle at the G1 and G2phases. This cell cycle arrest makes damaged cells take the time for DNArepair. However, if the DNA damage is irreparable, p53 induces celldeath by activating the apoptotic process, which is independent of p21.

Since the disruption of normal cell cycle regulation is the hallmark ofcancer, there are numerous opportunities for targeting checkpointcontrols to develop new therapeutic strategies for this disease. Suchstrategies include induction of checkpoint arrest leading to cytostasisand ultimately apoptosis, arrest of proliferating cells in stages of thecell cycle which may sensitize them to treatment with other therapeuticagents such as radiation, and targeting of therapies toward specificregulatory components of the cell cycle. Most anticancer agentsintervene at multiple points in the cell cycle. They have diversemechanisms of action and exhibit specificity in terms of the stage ofthe cell cycle in which they target i.e., DNA damaging anticancer agentslead to G1/S or G2/M arrest; microtubule targeting agents lead to Marrest; antimetabolites lead to S arrest; and topoisomerase inhibitorslead to S or G2/M arrest. In addition, some potentially successfultherapeutic strategies involve the use of agents that target cell cycleregulatory molecules. Chemical inhibitors of cdks, which exhibitspecificity for cdk1 and cdk2, can induce both G1 and G2 arrest as wellas apoptosis. Therefore, chemicals that specifically cause cell cyclearrest may be useful therapeutic agents for treating cancers and otherproliferating disorders irrespective of their target molecules.

The compounds of the invention are also useful for treating non-cancerdiseases or conditions which are HIF-mediated or VEGF-mediated. Suchdiseases or conditions include: atherosclerosis, (Couffinhal et al. Am JPathol 1997 150:1673-1685); diabetic retinopathy, (Boulton et al. Br JOphthalmol 1998 82:561-568); cardiac hypertophy, (Kakinuma et al.,Circulation 2001 103:2387-23945); vacular remodeling, (Semnza G L,Respir Res 2000 1:159-162); pulmonary hypertension, (Semnza G L, RespirRes 2000 1:159-162); pre-eclampsia, (Caniggia et al., Placenta 2000 21:S25-S30); arthritis, (Anthony et al., Arthritis and Rheumatism 2001 44:1540-1544); inflammatory disease, (Cramer et al., Cell 2003 112:645-657); and psoriasis (Bhushan et al., Br. J. Dermatol 1999 141:1054-1060).

Thus, compounds according to the present invention are usefultherapeutic agents, as single agents or when combined with otheranticancer therapies, for treating tumors and other proliferativedisorders, such as hyper-proliferative skin orders, via inhibition ofcell cycle progression.

DESCRIPTION OF THE FIGURES

FIG. 1 shows the S-phase arrest induced by YC-1 treatment in Hep3Bhepatoma cells. FIG. 1 a is the FACS data to analyze the celldistribution based on DNA content. FIG. 1 b is a dose-response curve forthe effect of 24 h YC-1 treatment on cell cycle. FIG. 1 c is a timecourse for the effect of 1 μM YC-1 on cell cycle. The cell cycleanalysis was performed using a Becton Dickinson FACStar flow cytometer.Cells (1-2×10⁶) were plated in 10 cm culture dishes at concentrationsdetermined to yield 70-80% confluence within 24 h. Cells were treatedwith DMSO or YC-1 and incubated for described time. After incubation,both adherent and floating cells were harvested, washed with 3 ml PBSand resuspended with 200 μl PBS, fixed in 75% ethanol for 30 min on ice.After washing with PBS, cells were labeled with propidium iodide (0.05mg/ml) in the presence of RNase A (0.5 mg/ml), incubated at roomtemperature in the dark for 30 min. DNA content was then analyzed usingFACStar flow cytometer, and then excited with an argon, water-cooledlaser emitting at 488 nm. Propidium iodide was detected using a 630±20nm band pass filter.

FIG. 2 shows cell death effect of YC-1 on Hep3B cells. The percentagesof viable cells were measured by MTT assay. Cells were incubated withthe indicated concentration of YC-1 for indicated time. Bars representthe mean of three separate experiments with the upper 95% confidenceinterval. *: p<0.05 vs. the control.

FIG. 3 is the apoptotic effect of YC-1. FIG. 3 a shows caspase-3activity. The activity of caspase-3 in Hep3B cell extracts that had beentreated with vehicle or 1 μM YC-1 for indicated time was measured byusing a caspase-3 activity assay kit. The activity of caspase-3 wasrepresented in nmoles of p-nitroaniline released per min and per ml ofcellular extract. Bars represent the mean of three separate experimentswith the upper 95% confidence interval. *: p<0.05 vs. the control. FIG.3 b shows PARP-cleavage. Hep3B cells were treated with 1, 2 μM YC-1 for90 h. PARP cleavage was analysed by immunoblotting with a mouseanti-PARP antibody. Proteins were visualized by EnhancedChemiluminescence Plus. The lane C is the control. Caspase-3 is anenzyme that digests the 113 kDa protein poly-ADP-ribose-polymerase(PARP) to form an inactive 89 kDa fragment. PARP is essential forDNA-replication in the S-phase and its absence leads to apoptosis. FIG.3 c shows the TUNEL assay. For quantification of apoptosis at singlecell level, based on labeling of DNA strand breaks, Hep3B cells weretreated with 1, 2 μM YC-1 for 90 h, and Ac-DEVD-CHO, Caspase-3 inhibitorwas treated before 1 h prior to treat YC-1.

FIGS. 4 a through 4 i show the protein amounts of HIF-1α and HIF-2α, andthe transcriptional activities of HIF (reporter assay). These indicateboth the protein suppression and transcriptional inhibition of HIF byvarious compounds of the invention under hypoxic conditions. FIG. 4 a isthe assay for comparison using YC-1.

FIGS. 5 a and 5 b represent, respectively, the data on toxicity in vitroand acute toxicity in vivo of four compounds of the invention. YC-1 isalso shown for comparison.

FIGS. 6 a and 6 b are plots of the tumor growth inhibition in vivo at,respectively, dosages of 30 mg/kg and 10 mg/kg for two compounds of theinvention. An untreated control and YC-1 are shown for comparison.

FIG. 7 is a plot summarizing the effects of some compounds according tothe invention on induced S-phase arrest of the cell cycle. The Y-axisrepresents the difference in S-phase population compared to the control(% S-phase of test compound minus % S-phase of the control).

FIGS. 8 through 17 are synthetic schemes for making compounds accordingto the invention.

SUMMARY OF THE INVENTION

The present invention relates to anti-tumor treatment and treatment ofother proliferative disorders or conditions by administration of a cellcycle arresting compound. In a particular aspect of the presentinvention the compounds are of Formula I:

wherein:

-   -   X is N or CR₆; Y is N or C;    -   R₁ is optionally substituted alkyl, optionally substituted aryl,        or optionally substituted heterocyclyl; or R₁ is absent if Y is        N;    -   R₂ and R₃ are independently chosen from hydrogen or optionally        substituted alkyl; or R₂ and R₃, together with the carbons to        which they are attached form an optionally substituted aromatic        or optionally substituted heteroaromatic ring; and    -   R₄ is optionally substituted aryl, optionally substituted        heterocyclyl, or optionally substituted alkyl;    -   R₆ is hydrogen, optionally substituted aryl, optionally        substituted heterocyclyl, or optionally substituted alkyl;    -   including single isomers, mixtures of isomers, and        pharmaceutically acceptable solvates and salts thereof;

In a particular aspect of the present invention, the compounds are ofFormula II:

wherein:

-   -   A is —NH—R₅—(CO)—, —(CO)—R₅—NH— or naphthyl; and    -   R₅ is optionally substituted phenyl or optionally substituted        pyridinyl.

Methods and pharmaceutical compositions for administering compounds ofFormula I or II to animals to inhibit tumor progression or treat otherproliferative disorders are also provided. The invention also providesmethods and pharmaceutical compositions for combining compounds ofFormula I or II with other anticancer agents or therapies. Compounds ofthe Formula III are also provided. Formula III

wherein

-   -   X is N, or CR₆; Y is N or C;    -   R₁ is optionally substituted heterocyclyl, provided that when        Y=N, and X=CH, R₁ is absent;

-   R₄ is aryl of 5 to 14 carbon atoms or alkyl of 1-10 carbon atoms;    -   except that when Y=N and X=CH, R₄ may be optionally substituted        heterocyclyl;    -   R₆ is hydrogen, optionally substituted aryl, optionally        substituted heterocyclyl, or optionally substituted alkyl;    -   and R₂ and R₃ are independently hydrogen, optionally substituted        alkyl, or R₂ and R₃ together with the carbon atoms to which they        are attached form an optionally substituted aryl or optionally        substituted heteroaryl ring.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

“Alkyl” is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof. Lower alkyl refers to alkyl groupsof from 1 to 5 carbon atoms. Examples of lower alkyl groups includemethyl, ethyl, propyl, i-propyl, butyl, s- and t-butyl and the like.Preferred alkyl groups are those of C₂₀ or below. More preferred alkylgroups are those of C₁₃ or below. Still more preferred alkyl groups arethose of C₆ and below. Cycloalkyl is a subset of alkyl and includescyclic hydrocarbon groups of from 3 to 13 carbon atoms. Examples ofcycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl,adamantyl and the like. In this application, alkyl refers to alkanyl,alkenyl and alkynyl residues; it is intended to includecyclohexylmethyl, vinyl, allyl, isoprenyl and the like. Alkylene isanother subset of alkyl, referring to the same residues as alkyl, buthaving two points of attachment. Examples of alkylene include ethylene(—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), dimethylpropylene (—CH₂C(CH₃)₂CH₂—)and cyclohexylpropylene (—CH₂CH₂CH(C₆H₁₃)—). When an alkyl residuehaving a specific number of carbons is named, all geometric isomershaving that number of carbons are intended to be encompassed; thus, forexample, “butyl” is meant to include n-butyl, s-butyl, i-butyl andt-butyl; “propyl” includes n-propyl and i-propyl.

The term “alkoxy” or “alkoxyl” refers to the group —O-alkyl, preferablyincluding from 1 to 8 carbon atoms of a straight, branched, cyclicconfiguration and combinations thereof attached to the parent structurethrough an oxygen. Examples include methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxyrefers to groups containing one to four carbons.

The term “substituted alkoxy” refers to the group —O-(substitutedalkyl). One preferred substituted alkoxy group is “polyalkoxy” or—O-(optionally substituted alkylene)-(optionally substituted alkoxy),and includes groups such as —OCH₂CH₂OCH₃, and glycol ethers such aspolyethyleneglycol and —O(CH₂CH₂O)_(x)CH₃, where x is an integer ofabout 2-20, preferably about 2-10, and more preferably about 2-5.Another preferred substituted alkoxy group is hydroxyalkoxy or—OCH₂(CH₂)_(y)OH, where y is an integer of about 1-10, preferably about1-4.

“Acyl” refers to groups of from 1 to 10 carbon atoms of a straight,branched, cyclic configuration, saturated, unsaturated and aromatic andcombinations thereof, attached to the parent structure through acarbonyl functionality. One or more carbons in the acyl residue may bereplaced by nitrogen, oxygen or sulfur as long as the point ofattachment to the parent remains at the carbonyl. Examples includeacetyl, benzoyl, propionyl, i-butyryl, t-butoxycarbonyl,benzyloxycarbonyl and the like. “Lower-acyl” refers to groups containing1 to 4 carbons and “acyloxy” refers to the group O-acyl.

The term “amino” refers to the group —NH₂. The term “substituted amino”refers to the group —NHR or —NRR where each R is independently selectedfrom the group: optionally substituted alkyl, optionally substitutedalkoxy, optionally substituted amino, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted heterocyclyl,acyl, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, e.g.,diethylamino, methylsulfonylamino, furanyl-oxy-sulfonamino.

“Aryl” and “heteroaryl” mean a 5-, 6- or 7-membered aromatic orheteroaromatic ring containing 0-4 heteroatoms selected from O, N or S;a bicyclic 9- or 10-membered aromatic or heteroaromatic ring systemcontaining 0-4 (or more) heteroatoms selected from O, N or S; or atricyclic 12- to 14-membered aromatic or heteroaromatic ring systemcontaining 0-4 (or more) heteroatoms selected from O, N or S. Thearomatic 6- to 14-membered aromatic carbocyclic rings include, e.g.,phenyl, naphthalene, indane, tetralin, and fluorene and the 5- to10-membered aromatic heterocyclic rings include, e.g., imidazole,oxazole, isoxazole, oxadiazole, pyridine, indole, thiophene,benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline,quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.

“Aralkyl” refers to a residue in which an aryl moiety is attached to theparent structure via an alkyl residue. Examples include benzyl,phenethyl, phenylvinyl, phenylallyl and the like. “Heteroaralkyl” refersto a residue in which a heteroaryl moiety is attached to the parentstructure via an alkyl residue. Examples include furanylmethyl,pyridinylmethyl, pyrimidinylethyl and the like.

“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.Fluorine, chlorine and bromine are preferred. Dihaloaryl, dihaloalkyl,trihaloaryl etc. refer to aryl and alkyl substituted with a plurality ofhalogens, but not necessarily a plurality of the same halogen; thus4-chloro-3-fluorophenyl is within the scope of dihaloaryl.

“Heterocycle” means a cycloalkyl or aryl residue in which one to four ofthe carbons is replaced by a heteroatom such as oxygen, nitrogen orsulfur. Examples of heterocycles that fall within the scope of theinvention include imidazoline, pyrrolidine, pyrazole, pyrrole, indole,quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran,benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl,when occurring as a substituent), tetrazole, morpholine, thiazole,pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline,isoxazole, oxadiazole, dioxane, tetrahydro furan and the like.“N-heterocyclyl” refers to a nitrogen-containing heterocycle as asubstituent residue. The term heterocyclyl encompasses heteroaryl, whichis a subset of heterocyclyl. Examples of N-heterocyclyl residues include4-morpholinyl, 4-thiomorpholinyl, 1-piperidinyl, 1-pyrrolidinyl,3-thiazolidinyl, piperazinyl and 4-(3,4-dihydrobenzoxazinyl). Examplesof substituted heterocyclyl include 4-methyl-1-piperazinyl and4-benzyl-1-piperidinyl.

“Substituted-” alkyl, aryl, heteroaryl and heterocyclyl referrespectively to alkyl, aryl, heteroaryl and heterocyclyl wherein one ormore (up to about 5, preferably up to about 3) hydrogen atoms arereplaced by a substituent independently selected from the group:optionally substituted alkyl (e.g., fluoroalkyl), optionally substitutedalkoxy, alkylenedioxy (e.g. methylenedioxy), optionally substitutedamino (e.g., alkylamino and dialkylamino), optionally substitutedamidino, optionally substituted aryl (e.g., phenyl), optionallysubstituted aralkyl (e.g., benzyl), optionally substituted aryloxy(e.g., phenoxy), optionally substituted aralkoxy (e.g., benzyloxy),carboxy (—COOH), carboalkoxy (i.e., acyloxy or —OOCR), carboxyalkyl(i.e., esters or —COOR), carboxamido, aminocarbonyl,benzyloxycarbonylamino (CBZ-amino), cyano, carbonyl, halogen, hydroxy,optionally substituted heteroaryl, optionally substituted heteroaralkyl,optionally substituted heteroaryloxy, optionally substitutedheteroaralkoxy, nitro, sulfanyl, sulfinyl, sulfonyl, and thio.

The term “sulfanyl” refers to the groups: —S-(optionally substitutedalkyl), —S-(optionally substituted aryl), —S-(optionally substitutedheteroaryl), and —S-(optionally substituted heterocyclyl).

The term “sulfinyl” refers to the groups: —S(O)—H, —S(O)-(optionallysubstituted alkyl), —S(O)-(optionally substituted amino),—S(O)-(optionally substituted aryl), —S(O)-(optionally substitutedheteroaryl), and —S(O)-(optionally substituted heterocyclyl).

The term “sulfonyl” refers to the groups: —S(O₂)—H, —S(O₂)-(optionallysubstituted alkyl), —S(O₂)-(optionally substituted amino),—S(O₂)-(optionally substituted aryl), —S(O₂)-(optionally substitutedheteroaryl), —S(O₂)-(optionally substituted heterocyclyl),—S(O₂)-(optionally substituted alkoxy), —S(O₂)-optionally substitutedaryloxy), —S(O₂)-(optionally substituted heteroaryloxy), and—S(O₂)-(optionally substituted heterocyclyloxy).

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl,” as defined below. Itwill be understood by those skilled in the art with respect to any groupcontaining one or more substituents that such groups are not intended tointroduce any substitution or substitution patterns that are stericallyimpractical, synthetically nonfeasible and/or inherently unstable.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. “Enantiomers” are a pair of stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term “(O)” is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric formsthat may be defined, in terms of absolute stereochemistry, as (R)- or(S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds of thisinvention and, which are not biologically or otherwise undesirable. Inmany cases, the compounds of this invention are capable of forming acidand/or base salts by virtue of the presence of amino and/or carboxylgroups or groups similar thereto. Pharmaceutically acceptable acidaddition salts can be formed with inorganic acids and organic acids.Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, or other organic acids known tobe useful for creation of phamaceutically acceptable acid additionsalts. Pharmaceutically acceptable base addition salts can be formedwith inorganic and organic bases. Inorganic bases from which salts canbe derived include, for example, sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum, and thelike; particularly preferred are the ammonium, potassium, sodium,calcium and magnesium salts. Organic bases from which salts can bederived include, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, basic ion exchange resins, and the like, specificallysuch as i-propylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine.

The term “therapeutically effective amount” or “effective amount” refersto that amount of a compound of Formula I or II that is sufficient toeffect treatment, as defined below, when administered alone or incombination with other anticancer therapies to a mammal in need of suchtreatment. More specifically, it is that amount that is sufficient toinhibit expression of HIF regulated genes or to induce cell cyclearrest. This, at the tumor site will inhibit tumor growth, tumorprogression and metastasis without adverse side effects. As used herein,“HIF-related genes” as used herein refer to the genes whose expressionsare regulated by HIF. The following genes are included in this genefamily; erythropoietin, transferrin, transferrin receptor,ceruloplasmin, vascular endothelial growth factor (VEGF), VEGF receptorFLT-1, transforming growth factor β3, plasminogen activator inhibitor 1,α1B adrenergic receptor, adrenomedullin, endothelin 1, nitric oxidesynthase 2, heme oxygenase 1, glucose transporter 1 & 3, hexokinase 1 &2, enolase 1, glyceraldehyde-3-phosphate dehydrogenase, phosphoglyceratekinase 1, phosphoglucokinase L, pyruvate kinase M, aldolase A & C, triosphosphate isomerase, lactate dehydrogenase A, carbonic anhydrase 9,adenylate kinase 3, prolyl-4-hydroxylase a1, insulin-like growth factor(IGF) 2, IGF-binding protein 1, 2 & 3, P21, Nip3, cyclin G2 anddifferentiated embryo chondrocyte 1, The term “animal” as used herein ismeant to include all mammals, and in particular humans. Such animals arealso referred to herein as subjects or patients in need of treatment.The therapeutically effective amount will vary depending upon thesubject and disease condition being treated, the weight and age of thesubject, the severity of the disease condition, the particular compoundof Formula I or II chosen, the dosing regimen to be followed, timing ofadministration, the manner of administration and the like, all of whichcan readily be determined by one of ordinary skill in the art.

The term “treatment” or “treating” means any treatment of a disease in amammal, including:

-   -   a) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   b) inhibiting the disease, that is, slowing or arresting the        development of clinical symptoms; and/or    -   c) relieving the disease, that is, causing the regression of        clinical symptoms.

Compounds of the Present Invention

The present invention is directed to the compounds represented byFormula I or II, which are selective to inhibit angiogenesis, and theexpressions of HIF-1α, HIF-2α, and the HIF-regulated genes in vitro andin vivo to induce cell cycle arrest, as follows:

wherein:

-   -   X is N or CR₆; Y is N or C;    -   R₁ is optionally substituted alkyl, optionally substituted aryl,        or optionally substituted heterocyclyl, or R₁ is absent if Y is        N;    -   R₂ and R₃ are independently chosen from hydrogen or optionally        substituted alkyl; or R₂ and R₃, together with the carbons to        which they are attached form an optionally substituted aromatic        or optionally substituted heteroaromatic ring; and    -   R₄ is optionally substituted aryl, optionally substituted        heterocyclyl, or optionally substituted alkyl;    -   R₆ is hydrogen, optionally substituted aryl, optionally        substituted heterocyclyl, or optionally substituted alkyl;    -   including single isomers, mixtures of isomers, and        pharmaceutically acceptable solvates and salts thereof; or        wherein:    -   A is —NH—R₅—(CO)—, —(CO)—R₅—NH— or naphthyl; and    -   R₅ is optionally substituted phenyl or optionally substituted        pyridinyl, including single isomers, mixtures of isomers, and        pharmaceutically acceptable solvates and salts thereof.

Compounds of the Formula III are also provided. Formula III

wherein

-   -   X is N, or CR₆; Y is N or C;    -   R₁ is optionally substituted heterocyclyl, provided that when        Y=N, and X=CH, R₁ is absent;    -   R₄ is aryl of 5 to 14 carbon atoms or alkyl of 1-10 carbon        atoms;    -   except that when Y=N and X=CH, R₄ may be optionally substituted        heterocyclyl;    -   R₆ is hydrogen, optionally substituted aryl, optionally        substituted heterocyclyl, or optionally substituted alkyl;    -   and R₂ and R₃ are independently hydrogen, optionally substituted        alkyl, or R₂ and R₃ together with the carbon atoms to which they        are attached form an optionally substituted aryl or optionally        substituted heteroaryl ring.        Nomenclature

The compounds of Formula I and II can be named and numbered (e.g., usingAutoNom version 2.1) as described below. For example, the compound ofFormula IA:

i.e., the compound according to Formula I where R₁ ishydroxymethylfuranyl-; R₂ and R₃ together with the carbons to which theyare attached form a fused benzo group; and R₄ is methyl, can be named[5-(1-methyl-1H-indazol-3-yl)-furan-2-yl]-methanol.

Synthesis of the Compounds of Formula I and II

The compounds of the invention can be synthesized utilizing techniqueswell known in the art from commercially available starting materials.See, e.g., U.S. Pat. Nos. 6,162,819; 6,518,294; and 5,574,168 andEuropean Patent Application No. 254, 241, each of which is incorporatedherein by reference in its entirety.

Benzimidazole derivatives may be synthesized by substitution on asuitable benzimidazole starting material with an appropriate alkyl, arylor heteroaryl-halide. Useful reaction conditions include carrying outthe condensation in the presence of cuprous iodide, a weak base, such asN,N′-dimethyl-ethylenediamine, and cesium carbonate.

YC-1, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole, a comparisoncompound to compounds of the present invention, may be manufactured byprior art techniques or is also available commercially. For example,YC-1 may be obtained from A.G. Scientific Inc. (San Diego, Calif.),Sigma RBI (St Louis, Mo., USA), or Alexis Biochemicals (San Diego,Calif.).

In addition, some of the compounds of the invention may be synthesizedwith reference to syntheses schematically shown in the figures.Referring to FIG. 8 there is shown a scheme for generally making 1-alkyland 1-aryl substituted indazoles, such as compounds identified as 5 and5a. Condensation of 1a and 1b produces the nitro ketone 2, which isselectively reduced to amino ketone 3. Nitration and reduction producethe cyclic product 4 that is then either reduced to form 5 or alkylated(or arylated) to form 5a. The compound 5a is also identified as CompoundA herein.

Referring to FIG. 9 there is shown a scheme for making 1- or2-substituted indazoles. Condensation of furan and an appropriatelysubstituted benzaldehyde leads to 6. Selective oxidation, reduction,nitration and cyclization sequentially produce 7, 8 and 9. AfterN-protection, carbonylation and deprotection, the indazole 11 isalkylated at the 1- and 2-positions, the isomers separated and reducedto produce 13a and 13b. Compound 13a is also identified as Compound Cherein.

Referring to FIG. 10, there are shown schemes for making 1-aryl and1-alkyl indazoles. Intermediate 11, described above is arylated andreduced to produce the 1-thienyl indazole 15. 3-iodo-indazole 16 isselectively arylated at the 1- and 3-positions, then reduced to producethe 1-phenyl indazole 19. The 1-methyl indazole 22 is similarlyproduced. Compound 22 is also identified as Compound D herein.

Referring to FIG. 11, there is shown a scheme for making 3-furanylindazoles. 3-Iodo-indazole 24 is sequentially alkylated and arylated atpositions 1- and 3- to produce 27a or 27b. The reagents 26a and 26b areformed from the appropriate furan.

FIGS. 12 a and 12 b illustrate schemes for making 3-arylated 1-benzylindazoles from a common precursor, 1-benzyl-3-iodoindazole 28, made from3-iodo-indazole 16. The reagents 29b and 29c are made by a methodanalogous to that shown for making reagent 29a from an appropriatehaloaryl compound. The 3-arylated compounds 30, 31 and 32 are made inone step from 28. Compound 31 is also identified as Compound B herein.

Referring to FIG. 13 there is shown another scheme for making1,3-substituted indazoles. Condensation, mild oxidation, selectivereduction of the nitro goup, nitration and cyclization result in1-furanyl-indazole 36. Benzylation and carbonylation produce the1-benzyl-3-furanyl indazole 39, also identified as YC-1. The furanylring is then reduced to produce the 3-tetrahyrofuranyl indazole 42.

Referring to FIG. 14 there are shown a scheme to produce 1-alkylindazoles and 1-aryl benzimidazoles. The 3-furanyl indazole 11N-alkylated and reduced to produce the N-ethyl or N-1-propyl indazole 44or 46. The benzimidazoles 49 and 51 are respectively formed fromisoindole 47 and an appropriate haloaryl compound 48a or 48b. Reductionproduces the 1-arylated benzimidazoles 50 and 52.

Referring to FIG. 15 there is shown a scheme for producing 1,3,substituted-indole. The 3-dimethylamino-indole 53 is N-alkylated,brominated, arylated, carbonylated and reduced to produce the indole 58.

FIG. 16 shows a scheme for making some compounds of the Formula II.Reduction of the aldehyde 59, followed by activation and condensationproduce the bicyclic compound 61. Oxidation, selective reduction of thenitro group, N-alkylation and deprotection results in the compound 65.

Referring to FIG. 17, there are shown two general schemes forsynthesizing intermediates useful for preparation of compounds of theinvention. Compound IV may be readily prepared by acylation methodsknown in the art. The group Ar is an aryl or heteroaryl group,optionally substituted with R_(s) which may a group defined herein underthe definition “substituted-”. Reduction with iron in aqueous aceticacid produces the amine IV which is then cyclized to the 3-substitutedindazole VI with sodium nitrite in acid, followed by stannous chloride.The intermediate VI is useful for preparing compounds according to theinvention.

Still referring to FIG. 17, 3-iodo-indazole VII is treated with thedihydroxyborane Ar′B(OH)₂ where Ar′ is aryl or heteroaryl, followed bycupric diacetate, yielding the 1-substituted iodo-indazole VIII. ThenVIII is treated with an appropriate tributyl-tin compoundR_(t)—Ar″—SnBu₃ in palladium catalyst. The group Ar″ is aryl orheteroaryl. The substituent R_(t) is a group defined herein under thedefinition “substituted-”. This produces the 1,3-substituted indazole IXwhich is a useful intermediate for making compounds according to theinvention. Ar and Ar″ are independently preferably heteroaryl and Ar′ ispreferably aryl.

It is understood that other schemes may be devised to produce compoundswithin the scope of the invention. It is understood also that it iswithin the skill of those of ordinary skill in the art, given thesereaction schemes, to select appropriate solvents, reaction temperatures,ratios, etc. to accomplish the steps indicated to produce a usefulamount of the indicated product.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure, generally within a temperature range from−100° C. to 110° C. Further, except as employed in the Examples or asotherwise specified, reaction times and conditions are intended to beapproximate, e.g., taking place at about atmospheric pressure within atemperature range of about −10° C. to about 110° C. over a period ofabout 1 to about 24 hours; reactions left to run overnight average aperiod of about 16 hours.

The terms “solvent”, “organic solvent” or “inert solvent” each mean asolvent inert under the conditions of the reaction being described inconjunction therewith [including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like]. Unless specified to the contrary, thesolvents used in the reactions of the present invention are inertorganic solvents.

Isolation and purification of the compounds and intermediates describedherein can be effected, if desired, by any suitable separation orpurification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation procedurescan be had by reference to the examples herein below. However, otherequivalent separation or isolation procedures can, of course, also beused.

When desired, the (R)- and (S)-isomers may be resolved by methods knownto those skilled in the art, for example by formation ofdiastereoisomeric salts or complexes which may be separated, forexample, by crystallization; via formation of diastereoisomericderivatives which may be separated, for example, by crystallization,gas-liquid or liquid chromatography; selective reaction of oneenantiomer with an enantiomer-specific reagent, for example enzymaticoxidation or reduction, followed by separation of the modified andunmodified enantiomers; or gas-liquid or liquid chromatography in achiral environment, for example on a chiral support, such as silica witha bound chiral ligand or in the presence of a chiral solvent. Forexample, a compound of Formula I or II can be dissolved in a loweralkanol and placed on a Chiralpak AD (205×20 mm) column (ChiralTechnologies, Inc.) conditioned for 60 min at 70% EtOAc in hexane. Itwill be appreciated that where the desired enantiomer is converted intoanother chemical entity by one of the separation procedures describedabove, a further step may be required to liberate the desiredenantiomeric form. Alternatively, specific enantiomer may be synthesizedby asymmetric synthesis using optically active reagents, substrates,catalysts or solvents, or by converting one enantiomer to the other byasymmetric transformation.

While it is well known that pharmaceuticals must meet pharmacopoeiastandards before approval and/or marketing, and that synthetic reagentsand precursors should not exceed the limits prescribed by pharmacopoeiastandards, final compounds prepared by a process of the presentinvention may have minor, but detectable, amounts of such materialspresent, for example at levels in the range of 95% purity with no singleimpurity greater than 1%. These levels can be detected, e.g., byemission spectroscopy. It is important to monitor the purity ofpharmaceutical compounds for the presence of such materials, whichpresence is additionally disclosed as a method of detecting use of asynthetic process of the invention.

Preferred Processes and Last Steps

A racemic mixture of isomers of a compound of Formula I or II is placedon a chromatography column and separated into (R)- and (S)-enantiomers.

A compound of Formula I or II is contacted with a pharmaceuticallyacceptable base to form the corresponding base addition salt.

A pharmaceutically acceptable acid addition salt of Formula I or II iscontacted with an acid to form the corresponding compound of Formula Ior II. A compound of Formula I or II is contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalt.

A pharmaceutically acceptable acid addition salt of Formula I or II iscontacted with a base to form the corresponding free base of Formula Ior II.

Preferred Compounds

Preferred for the compounds, pharmaceutical formulations, methods ofmanufacture and use of the present invention are the followingcombinations and permutations of substituent groups of Formula I(sub-grouped, respectively, in increasing order of preference).

In a particular embodiment, X is N, and Y is C.

In another embodiment, X is CH and Y is N.

In one embodiment, R₁ is furanyl; phenyl; pyridinyl; thiophenyl; benzyl;diazole; triazole; tetrahydrofuranyl; or pyrrolyl-, each of which may beoptionally substituted with one, two or three (especially one) of thefollowing groups:

-   -   lower-alkyl (especially methyl);    -   amino-substituted lower-alkyl (especially aminomethyl-);    -   hydroxy-substituted lower-alkyl- (especially hydroxymethyl-,        hydroxyethyl-, 1-hydroxy-1-methyl-ethyl-; or        hydroxyethoxymethyl-);    -   (lower-alkoxy)methyl- (especially methoxymethyl- or        ethoxymethyl-); or    -   (lower-alkyl)sulfanyl- (especially methylsulfanyl-).

In another embodiment, R₁ is optionally substituted benzyl or optionallysubstituted phenyl.

More particularly, R₁ is hydroxymethylpyridinyl-; hydroxymethylphenyl-;hydroxymethylfuranyl-; aminomethylfuranyl-; methoxymethylfuranyl-;hydroxy-ethoxymethyl-furanyl-; (1-hydroxy-ethyl)-furanyl-;(1-hydroxy-1-methyl-ethyl)-furanyl-; hydroxymethyltetrahydrofuranyl-;hydroxymethylthiophenyl-; hydroxymethylpyrrolyl-; orhydroxymethyl-N-methyl-pyrrolyl.

In another embodiment, R₁ is optionally substituted benzyl or optionallysubstituted phenyl.

In another embodiment, R₁ is optionally substituted alkyl, preferablylower alkyl.

In one embodiment, R₂ and R₃ are hydrogen.

In another embodiment, R₂ and R₃, together with the carbons to whichthey are attached, form a fused benzo- or pyridino ring, which may beoptionally substituted with one or more of the following groups: halo(especially fluoro or chloro); optionally substituted lower-alkyl(especially methyl or trifluoromethyl); lower-alkoxy (especiallymethoxy); hydroxy; cyano; nitro; or optionally substituted amino(especially amino, methylamino, or acetylamino).

In a particular embodiment, R₄ is optionally substituted phenyl;optionally substituted benzyl; optionally substituted cyclohexylmethyl-;optionally substituted phenethyl-; optionally substitutedpyridinylmethyl-; optionally substituted furanyl-; or optionallysubstituted pyrrolyl- optionally substituted thienyl, optionallysubstituted triazole, optionally substituted thienylmethyl, optionallysubstituted diazole; optionally substituted alkyl. More particularly,the aforementioned ring systems may be substituted with one or more ofthe following groups: halo (especially fluoro or chloro); optionallysubstituted lower-alkyl (especially methyl or trifluoromethyl);lower-alkoxy (especially methoxy); hydroxy; cyano; nitro; or optionallysubstituted amino.

In another embodiment, R₄ is optionally substituted alkyl, preferablylower alkyl.

A preferred class of compounds includes those in which R₁ is optionallysubstituted heterocyclyl, provided that when Y=N and X=CH, R₁ is absent;and R₄ is aryl of 5 to 14 carbon atoms or alkyl of 1 to 10 carbon atoms,except that when Y=N and X=CH, R₁ may be optionally substitutedheterocyclyl. In this class R₂ and R₃ are independently H, optionallysubstituted alkyl, or R₂ and R₃ together with the carbon atoms to whichthey are attached form an optionally substituted aryl or optionallysubstituted heteroaryl ring. Subclasses of this preferred class includethose in which X=N, Y=C and R₄ is alkyl of 1 to 10 carbon atoms; X=N,Y=C and R₄ is aryl of 5 to 14 carbon atoms; X=CH and Y=N; and R₂ and R₃are joined to form a 6-membered aryl ring.

More preferred (individually and collectively) as novel compounds of thepresent invention, including their formulations, methods of manufactureand use, are the following:

-   [5-(1-Methyl-1H-indazol-3-yl)-furan-2-yl]-methanol (Compound A);-   [5-(1H-Indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-1H-pyrazol-3-yl)-furan-2-yl]-methanol;-   1-Benzyl-1H-indazole;-   1-Benzyl-3-furan-2-yl-1H-indazole;-   1-Benzyl-3-(5-methyl-furan-2-yl)-1H-indazole;-   1-Benzyl-3-(5-methoxymethyl-furan-2-yl)-1H-indazole;-   2-[5-(1-Benzyl-1H-indazol-3-yl)-furan-2-yl]-propan-2-ol;-   2-[5-(1-Benzyl-1H-indazol-3-yl)-furan-2-ylmethoxy]-ethanol;-   1-[5-(1-Benzyl-1H-indazol-3-yl)-furan-2-yl]-ethanol;-   [5-(1-Benzyl-1H-indazol-3-yl)-tetrahydro-furan-2-yl]-methanol;-   C-[5-(1-Benzyl-1H-indazol-3-yl)-furan-2-yl]-methylamine;-   [5-(1-Benzyl-1H-indazol-3-yl)-furan-3-yl]-methanol;-   [5-(1-Benzyl-1H-indazol-3-yl)-thiophen-2-yl]-methanol;-   [5-(1-Benzyl-1H-indazol-3-yl)-1-methyl-1H-pyrrol-2-yl]-methanol;-   [5-(1-Benzyl-1H-indazol-3-yl)-1H-pyrrol-2-yl]-methanol;-   [4-(1-Benzyl-1H-indazol-3-yl)-phenyl]-methanol;-   [6-(1-Benzyl-1H-indazol-3-yl)-pyridin-3-yl]-methanol;-   [5-(1-Benzyl-1H-indazol-3-yl)-pyridin-2-yl]-methanol;-   [3-(1-Benzyl-1H-indazol-3-yl)-phenyl]-methanol;-   [4-(1-Benzyl-1H-indazol-3-yl)-pyridin-2-yl]-methanol;-   [6-(1-Benzyl-1H-indazol-3-yl)-pyridin-2-yl]-methanol;-   [6-(1-Benzyl-1H-indazol-3-yl)-pyridin-2-yl]-methanol;-   4-[3-(5-Hydroxymethyl-furan-2-yl)-indazol-1-ylmethyl]-phenol;-   {5-[1-(4-Amino-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(4-Fluoro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(4-Nitro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(4-Trifluoromethyl-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(4-Methoxy-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(4-Chloro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(4-Cyano-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(3-Amino-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(3-Fluoro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(3-Nitro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(3-Trifluoromethyl-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(3-Methoxy-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(3-Chloro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(3-Cyano-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(3-methyl-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(2-Amino-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(2-Fluoro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(2-Nitro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(2-Trifluoromethyl-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(2-Methoxy-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(2-Chloro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(2-Cyano-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(2-Methyl-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   3-[3-(5-Hydroxymethyl-furan-2-yl)-indazol-1-ylmethyl]-phenol;-   2-[3-(5-Hydroxymethyl-furan-2-yl)-indazol-1-ylmethyl]-phenol;-   [5-(1-Pyridin-2-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Pyridin-3-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Pyridin-4-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Cyclohexylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Furan-3-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Thiophen-3-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   {5-[1-(1-Methyl-1H-pyrrol-3-ylmethyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(1H-Pyrrol-3-ylmethyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   [5-(1-Furan-2-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Thiophen-2-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   {5-[1-(1-Methyl-1H-pyrrol-2-ylmethyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   {5-[1-(1H-Pyrrol-2-ylmethyl)-1H-indazol-3-yl]-furan-2-yl}-methanol;-   [5-(1-Phenethyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-furan-2-yl]-methanol;-   [5-(1-Phenyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-5-methyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-5-trifluoromethyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-5-hydroxy-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-5-amino-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-5-fluoro-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-5-methoxy-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-5-nitro-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-5-cyano-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-5-chloro-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-6-methyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-6-trifluoromethyl-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-6-hydroxy-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-6-amino-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-6-fluoro-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-6-methoxy-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-6-nitro-1H-indazol-3-yl)-furan-2-yl]-methanol;-   [5-(1-Benzyl-6-cyano-1H-indazol-3-yl)-furan-2-yl]-methanol; or-   [5-(1-Benzyl-6-chloro-1H-indazol-3-yl)-furan-2-yl]-methanol.    {5-[(3-Benzyl)-1H-indazol-3-yl-]-furan-2-yl}-methanol-   (2′-Hydroxymethyl)-(2-benzyl)-1H-indazo[6,7:5′4′]furan-   {5-[V-benzimidazol-1-yl]-furan-2-yl}-methanol-   {5-[(7-Phenyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[1-Methyl-1H-benzimidazol-4-yl]-furan-2-yl}-methanol-   {5-[1-Ethyl-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[1-(Prop-2-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[1-(2-Methyl-prop-2-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(Furan-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(Thien-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(N-Methyl-pyrrol-2′yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(Furan-3′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl]furan-2-yl}-methanol-   {5-[(1-(Thien-3′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(N-Methyl-pyrrol-3′yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(Oxa-3′,4′-diazol-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(Pyrrol-1′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(Thia-3′,4′-diazol-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(4′-Methyl-1′,2′,4′-triazol-5′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,2′,4′-Triazol-1′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,2′,4′-Triazol-4′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Oxazol-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Thiazol-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′-Methyl-1′,3′-diazol-2′-yl)-1H    methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Oxazol-5′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Thiazol-5′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′-Methyl-1′3′-diazol-5′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Oxazol-4′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Thiazol-4′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′-Methyl-1′,2′-diazol-5′-yl)-methyl)-1H1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′-Methyl-1′,3′-diazol-4′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Diazol-1′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′-Methyl-1′,2′-diazol-4′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′-Methyl-1′,2′-diazol-3′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,2′-Diazol-1′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(Furan-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(Thien-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(N-methyl-pyrrol-2′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(Pyrrol-1′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(Furan-3′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(Thien-3′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(N-Methyl-pyrrol-3′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(4′-Methyl-1′,2′,4′-triazol-5′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,2′,4′-Triazol-4′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(Thia-3′-4′diazol-2′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Oxazol-2′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Thiazol-2′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′-Methyl-1′,3′-diazol-2′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Oxazol-4′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Thiazol-4′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′-Methyl-1,3′-diazol)-4′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3-Diazol-1′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Oxazol-5′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,3′-Thiazol-5′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′-Methyl-1′,3′-diazol-5′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′-Methyl-1′,2′-diazol-5′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′,2′-Diazol-1′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′-Methyl-1′,2′-diazol-3′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[(1-(1′-Methyl-1′,2′-diazol-4′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[1-Benzyl-1H-indazol-3-yl]-furan-3-yl}-methanol-   {5-[1-Benzyl-1H-indazol-3-yl]-thien-3-yl}-methanol-   {N-Methyl-5-[benzyl-1H-indazol-3-yl]-pyrrol-3-yl}-methanol-   {4-[1-Benzyl-1H-indazol-3-yl]-furan-2-yl}-methanol-   {4-[1-Benzyl-1H-indazol-3-yl]-thien-2-yl}-methanol-   {N-Methyl-4-[1-benzyl-1H-indazol-3-yl]-pyrrol-2-yl}-methanol-   {4-Methyl-5-[1-benzyl-1H-indazol-3-yl]-1,2,4-triazol-3-yl}-methanol-   {5-[1-Benzyl-1H-indazol-3-yl]-thien-2-yl}-methanol-   {N-Methyl-5-[1-benzyl-1H-indazol-3-yl]-pyrrol-2-yl}-methanol    (Compound B)-   {1-[1-Benzyl-1H-indazol-3-yl]-1,2,4-triazol-3-yl}-methanol-   {1-[1-Benzyl-1H-indazol-3-yl]-pyrrol-3-yl}-methanol-   {5-[1-Benzyl-1H-indazol-3-yl]-oxa-3-4-diazol-2-yl}-methanol-   {5-[1-Benzyl-1H-indazol-3-yl]-thia-3,4-diazol-2-yl}-methanol-   {1-[1-Benzyl-1H-indazol-3-yl]-1,2-diazol-4-yl}-methanol-   {1-[1-Benzyl-1H-indazol-3-yl]-1,2-diazol-3-yl}-methanol-   {1-Methyl-3-[1-benzyl-1H-indazol-3-yl]-1,2-diazol-5-yl}-methanol-   {1-Methyl-5-[1-benzyl-1H-indazol-3-yl]-1,2-diazol-3-yl}-methanol-   {1-[1-Benzyl-1H-indazol-3-yl]-1,3-diazol-4-yl}-methanol-   {2-[1-Benzyl-1H-indazol-3-yl]-1,3-oxazol-5-yl}-methanol-   {2-[1-Benzyl-1H-indazol-3-yl]-1,3-thiazol-5-yl}-methanol-   {1-Methyl-2-[1-benzyl-1H-indazol-3-yl]-1,3-diazol-5-yl}-methanol-   {5-[1-Benzyl-1H-indazol-3-yl]-1,3-oxazol-5-yl}-methanol-   {2-[1-Benzyl-1H-indazol-3-yl]-1,3-oxazol-4-yl}-methanol-   {2-[1-Benzyl-1H-indazol-3-yl]-1,3-thiazol-4-yl}-methanol-   {1-Methyl-2-[1-benzyl-1H-indazol-3-yl]-1,3-diazol-4-yl}-methanol-   {1-Methyl-5-[1-benzyl-1H-indazol-3-yl]-1,3-diazol-2-yl}-methanol-   {4-[1-Benzyl-1H-indazol-3-yl]-1,3-oxazol-2-yl}-methanol-   {4-[1-Benzyl-1H-indazol-3-yl]-1,3-thiazol-2-yl}-methanol-   {1-Methyl-4-[1-benzyl-1H-indazol-3-yl]-1,3-diazol-2-yl}-methanol-   {5-[1-Benzyl-1H-indazol-3-yl]-1,3-thiazol-2-yl}-methanol-   {2-[1-Phenyl-1H-indazol-3-yl]-1,3-oxazol-5-yl}-methanol-   {2-[1-Phenyl-1H-indazol-3-yl]-1,3-thiazol-5-yl}-methanol-   {1-Methyl-2-[1-phenyl-1H-indazol-3-yl]-1,3-diazol-5-yl}-methanol-   {2-[1-Phenyl-1H-indazol-3-yl]-1,3-oxazol-4-yl}-methanol-   {2-[1-Phenyl-1H-indazol-3-yl]-1,3-thiazol-4-yl}-methanol-   {1-Methyl-2-[1-phenyl-1H-indazol-3-yl]-1,3-diazol-4-yl}-methanol-   {1-[1-Phenyl-1H-indazol-3-yl]-1,3-diazol-4-yl}-methanol-   {4-[1-Phenyl-1H-indazol-3-yl]-1,3-oxazol-2-yl}-methanol-   {4-[1-Phenyl-1H-indazol-3-yl]-1,3-thiazol-2-yl}-methanol-   {1-Methyl-4-[1-phenyl-1H-indazol-3-yl]-1,3-diazol-2-yl}-methanol-   {5-[1-Phenyl-1H-indazol-3-yl]-1,3-oxazol-2-yl}-methanol-   {5-[1-Phenyl-1H-indazol-3-yl]-1,3-thiazol-2-yl}-methanol-   {1-Methyl-5-[1-phenyl-1H-indazol-3-yl]-1,3-diazol-2-yl}-methanol-   {5-[1-Phenyl-1H-indazol-3-yl]-furan-3-yl}-methanol-   {5-[1-Phenyl-1H-indazol-3-yl]-thien-3-yl}-methanol-   {N-Methyl-5-[1-phenyl-1H-indazol-3-yl]-pyrrol-3-yl}-methanol-   {4-[1-Phenyl-1H-indazol-3-yl]-furan-2-yl}-methanol-   {4-[1-Phenyl-1H-indazol-3-yl]-thien-2-yl}-methanol-   {N-Methyl-4-[1-phenyl-1H-indazol-3-yl]-pyrrol-2-yl}-methanol-   {5-[1-Phenyl-1H-indazol-3-yl]-furan-2-yl}-methanol-   {5-[1-Phenyl-1H-indazol-3-yl]-thien-2-yl}-methanol-   {N-Methyl-5-[1-phenyl-1H-indazol-3-yl]-pyrrol-2-yl}-methanol    (Compound E)-   {4-Methyl-5-[1-phenyl-1H-indazol-3-yl]-1,2,4-triazol-3-yl}-methanol-   {1-[1-Phenyl-1H-indazol-3-yl]-1,2,4-triazol-3-yl}-methanol-   {N-[1-Phenyl-1H-indazol-3-yl]-pyrrol-3-yl}-methanol-   {5-[1-Phenyl-1H-indazol-3-yl]-oxadiazol-2-yl}-methanol-   {5-[1-Phenyl-1H-indazol-3-yl]-thiadiazol-2-yl}-methanol-   {2-Methyl-5-[1-phenyl-1H-indazol-3-yl]-1,2-diazol-3-yl}-methanol-   {1-Methyl-3-[1-phenyl-1H-indazol-3-yl]-1,2-diazol-5-yl}-methanol-   {1-[1-Phenyl-1H-indazol-3-yl]-1,2-diazol-4-yl}-methanol-   {1-[1-Phenyl-1H-indazol-3-yl]-1,2-diazol-3-yl}-methanol-   {5-[4-Phenyl-1H-benzimidazol-1-yl]-furan-2-yl}-methanol-   {N-Methyl-5-[1H-benzimidazol-1-yl]-pyrrol-2-yl}-methanol-   {1-Methyl-2-[1H-benzimidazol-1-yl]-1,3-diazol-5-yl}-methanol-   {3-[1H-Benzimidazol-1-yl]-benzyl alcohol-   {N-Methyl-5-[1H-benzimidazol-1-yl-methyl]-pyrrol-2-yl}}-methanol-   [5-(1-Thiophen-2-yl-methyl-1H-indazol-3-yl)-furan-2-yl]-methanol    (Compound C)-   (3-(1H-Benzo[d]imidazol-1-yl)phenyl)-methanol-   2-(3-(5-(Hydroxymethyl)furan-2-yl)-1H-indazol-1-yl)-acetic acid-   2-(3-(5-(Hydroxymethyl)-furan-2-yl)-1H-indazol-1-yl)-ethanol-   2-((5-(1-Methyl-1H-indazol-3-yl)-furan-2-yl)methoxy)-ethanol-   (1-Methyl-5-(1-methyl-1H-indazol-3-yl)-1H-pyrrol-2-yl)-methanol    (Compound D)-   {N-Methyl-5-[1-thiophen-2-yl-methyl-1H-indazol-3-yl]-pyrrol-2-yl}-methanol

Preferred for the compounds, pharmaceutical formulations, methods ofmanufacture and use of the present invention are the following compoundsof Formula II:

-   [5-(4-Benzyl-naphthalen-1-yl)-furan-2-yl]-methanol;-   (2-Benzylamino-phenyl)-(5-hydroxymethyl-furan-2-yl)-methanone; or-   1-[2-(5-Hydroxymethyl-furan-2-ylamino)-phenyl]-2-phenyl-ethanone.

Also preferred for the compounds, pharmaceutical formulations, methodsof manufacture and use of the present invention are the followinganalogs of the compounds of Formula I or II:

-   [5-(7-Phenyl-pyrazolo[1,5-a]pyridin-2-yl)-furan-2-yl]-methanol or-   2-Benzyl-2H-8-oxa-1,2-diaza-as-indacen-7-ol.

Utility, Testing and Administration

Utility

The present invention is based on the surprising discovery thatcompounds of Formula I or II exhibit an antitumor effect in vivo eitherby inhibiting HIF activity or by arresting the cell cycle essential fortumor growth and metastasis.

Accordingly, one aspect of the present invention provides a method ofinhibiting HIF-1α or HIF-2α expression in tumor cells or tissues, and toinduce cell cycle arrest leading to apoptosis, comprising contacting thetumor cells or tissues with a composition comprising a compound ofFormula I or II at an effective amount for inducing cell cycle arrest.

Another aspect of the present invention provides a method of inhibitingHIF-regulated gene expression in tumor cells or tissues, comprisingcontacting the tumor cells or tissues with a composition comprising acompound of Formula I or II at an effective amount for inhibiting HIF-regulated gene expression.

A further aspect of the present invention provides a method ofinhibiting tumor growth in animal tissues, comprising contacting theanimal tissues with a composition comprising a compound of Formula I orII at an effective amount for inhibiting tumor growth.

Yet another aspect of the present invention provides a method ofinhibiting tumor progression and metastasis in animal tissues,comprising contacting the animal tissues with a composition comprising acompound of Formula I or II at an effective amount for inhibiting tumorprogression and metastasis.

The present invention is broadly applicable to a variety of uses whichinclude single agent or a component in combination therapy to treatHIF-mediated disorders or conditions with accompanying undesiredangiogenesis, such as solid and blood-borne tumors including but notlimited to melanomas, carcinomas, sarcomas, rhabdomyosarcoma,retinoblastoma, Ewing sarcoma, neuroblastoma, osteosarcoma, andleukemia.

Testing

Compounds of the invention have an inhibitory effect on the expressionof HIF-1α and HIF-2α and on the induction of VEGF, aldolase A, andenolase 1 in cancer cells cultured under hypoxic conditions. In vivo,treatment halts the growth of xenografted tumors originating fromhepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma, andneuroblastoma cells. Tumors from treated mice show fewer blood vesselsand reduced expression of HIF-1α and HIF-2α proteins and HIF-regulatedgenes than tumors from vehicle-treated mice.

The compounds induce cell cycle arrest as shown in Hep3B liver tumorcells. After application of 1 μM into cultures of Hep3B cells, typicallyin 48 hours, 28% of the cells were in the G0/G1 phases, 15% in the G2/Mphases, 57% in the S phase, and a small percentage were characterized asbeing in the sub-G1 phase. In the control, typically 60% of the cellswere in the G0/G1 phases, 16% in the G2/M phases, and 30% in theS-phase. This shows substantial arrest of the cell cycle such thatalmost double the percentage of cells are in the S-phase. This effectwas dose dependent up to 5 μM for YC-1 in these cultures. Referring toFIG. 1, for YC-1 it can be seen that in plots of cell count vs. DNAcontent, the percentage of cells in the S-phase steadily increased withtime after application.

Compounds of Formula I or II can be evaluated for efficacy using themethods described above. In addition, compounds of the invention haveefficacy in in a cell viability assay using human cancer cells. Thecells are treated with a compound of Formula I or II (at concentrationsranging from 0.5-2 μM) and buffer. Cellular viability is measured at 24,48, and 72 hours. Treatment with the compound results in a notabledecrease in cell viability.

Administration

The compounds of Formula I or II are administered at a therapeuticallyeffective dosage, e.g., a dosage sufficient to provide treatment for thedisease states previously described. While human dosage levels have yetto be optimized for the compounds of the invention, generally, a dailydose is from about 0.05 to 100 mg/kg of body weight, preferably about0.10 to 10.0 mg/kg of body weight, and most preferably about 0.15 to 1.0mg/kg of body weight. Thus, for administration to a 70 kg person, thedosage range would be about 3.5 to 7000 mg per day, preferably about 7.0to 700.0 mg per day, and most preferably about 10.5 to 70 mg per day.The amount of active compound administered will, of course, be dependenton the subject and disease state being treated, the severity of theaffliction, the manner and schedule of administration and the judgmentof the prescribing physician; for example, a likely dose range for oraladministration would be about 700 to 7000 mg per day, whereas forintravenous administration a likely dose range would be about 70 to 700mg per day, the active agents being selected for longer or shorterplasma half-lives, respectively.

The nonspecific cytotoxicity of the compounds according to the inventionis generally greater than 90% survival tested in vitro by MTT assay at aconcentration of 5 μg/ml. In the assay cells are plated in cultureplates at a density of 2×10⁴ cells per well. After stabilizing for 24hr., Hep3B cells are treated with test compound at a concentration of 5μg/ml, then assayed after 24-hr. for viability. MTT-labeling reagent(final conc. 0.5 mg/ml) is added to each well and 4 hours later thecells are lysed with i-propyl alcohol. Absorbance is measured at 570 nm.

Administration of the compounds of the invention or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration for agents that serve similar utilities including, butnot limited to, orally, subcutaneously, intravenously, intranasally,topically, transdermally, intraperitoneally, intramuscularly,intrapulmonarilly, vaginally, rectally, or intraocularly. Oral andparenteral administration are customary in treating the indications thatare the subject of the present invention.

Pharmaceutically acceptable compositions include solid, semi-solid,liquid and aerosol dosage forms, such as, e.g., tablets, capsules,powders, liquids, suspensions, suppositories, aerosols or the like. Thecompounds can also be administered in sustained or controlled releasedosage forms, including depot injections, osmotic pumps, pills,transdermal (including electrotransport) patches, and the like, forprolonged and/or timed, pulsed administration at a predetermined rate.Preferably, the compositions are provided in unit dosage forms suitablefor single administration of a precise dose.

The compounds can be administered either alone or more typically incombination with a conventional pharmaceutical carrier, excipient or thelike (e.g., mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin,sucrose, magnesium carbonate, and the like). If desired, thepharmaceutical composition can also contain minor amounts of nontoxicauxiliary substances such as wetting agents, emulsifying agents,solubilizing agents, pH buffering agents and the like (e.g., sodiumacetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate,triethanolamine acetate, triethanolamine oleate, and the like).Generally, depending on the intended mode of administration, thepharmaceutical formulation will contain about 0.005% to 95%, preferablyabout 0.5% to 50% by weight of a compound of the invention. Actualmethods of preparing such dosage forms are known, or will be apparent,to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa.

In addition, the compounds of the invention can be co-administered withother active medicinal agents and/or administered in conjunction withother anticancer, antitumor, or anti-proliferative disease therapies.Such therapies include, but are not limited to, radiation therapy,chemotherapy, immunotherapy, laser/microwave thermotherapy, and genetherapy using antisense DNA and RNA. See Moeller et al., Cancer Cell2004 5:429-441. Suitable additional active agents include, for example:with alfa interferons such as Interferon alfa-2b; alkylators such asasaley, AZQ, BCNU, busulfan, carboxyphthalatoplatinum, CBDCA, CCNU,CHIP, chlorambucil, chlorozotocin, clomesone, cyclodisone,cyclophosphamide, dacarbazine, dianhydrogalactitol, fluorodopan,hepsulfam, hycanthone, L-PAM, melphalan, methyl CCNU, mitomycin C,mitozolamide, nitrogen mustard, PCNU, piperazine alkylator,piperazinedione, pipobroman, porfiromycin, spirohydantoin mustard,temozolomide, teroxirone, tetraplatin, thio-tepa, triethylenemelamine,uracil nitrogen mustard, and Yoshi-864; anthracyclines such asdoxorubicin, cyanomorpholinodoxorubicin, mitoxantrone, idarubicin,doxorubicin liposomal, valrubicin, epirubicin, daunomycin, anddaunorubicin liposomal; antibiotics such as dactinomycin, actinomycin D,bleomycin, and daunorubicin; aromatases inhibitor such as anastrozoleand letrozole; covalent conjugate of recombinant methionyl human GCSFand monomethoxypolyethylene glycol; cyclo-oxygenase inhibitors such ascelecoxib; diluents such as Elliott's B Solution; enzymes such asAsparaginase; erythropoiesis stimulating proteins such as Epoetin alfaand Darbepoetin alfa; estrogen receptor modulators such as tamoxifen andfulvestrant; folate antagonists such as methotrexate; granulocyte colonystimulating factors such as Filgrastim; hormonals such as anastrozole;inorganic arsenates such as arsenic trioxide; microtubule inhibitorssuch as vincristine, vinblastine, paclitaxel, vinorelbine, anddocetaxel; modifiers such as leucovorin and dexrazoxane; monoclonalantibodies such as anti-CD20 (Rituximab, ⁹⁰Y-ibrtumomab tiuexetan, and¹³¹-tositumomab), anti-CD22 (Epratuzumab and ⁹⁰Y-epratuzumab),anti-HLA-DR (Remitogen), anti-HER2/NEU (Trastuzumab), anti-CD33(Gemtuzumab ozogamicin), anti-CD52 (Alemtuzumab), anti-carcinoembryonicantigen (⁹⁰Y-CEA-cide), anti-epithelial cellular-adhesion molecule(Edrecolomab), anti-epidermal growth-factor receptor (Cetuximab, h-R3,and ABX-EGF), anti-VEGF (Bevacizumab), anti-VEGFR2 (IMC-1C11), anti-A33(huA33), anti-G250/MN (G250), anti-Lewis Y antigen (SGN-15 and Hu3S193),and anti-GD3 (KW-2871); nitrosoureas such as procarbazine, lomustine,CCNU, carmustine, estramustine, and carmustine with Polifeprosan 20Implant; nucleoside analogues such as mercaptopurine, 6-MP,fluorouracil, 5-FU, thioguanine, 6-TG, cytarabine, floxuridine(intraarterial), fludarabine, pentostatin, cladribine, pentostatin,gemcitabine, capecitabine, gemcitabine, and cytarabine liposomal;osteoclast inhibitors such as pamidronate; platinums such ascarboplatin, cisplatin, and oxaliplatin; retinoids such as tretinoin,ATRA, alitretinoin, and bexarotene capsules gel; stem cell stimulatorssuch as Oprelvekin; topoisomerase 1 inhibitors such as topotecan andirinotecan; topoisomerase 2 inhibitors such as etoposide, (VP-16),teniposide, (VM-26), and etoposide phosphate; tyrosine kinase inhibitorssuch as imatinib mesylate; urate-oxidase enzymes such as Rasburicase;and hydroxyurea.

In one preferred embodiment, the compositions will take the form of apill or tablet and thus the composition will contain, along with theactive ingredient, a diluent such as lactose, sucrose, dicalciumphosphate, or the like; a lubricant such as magnesium stearate or thelike; and a binder such as starch, gum acacia, polyvinylpyrrolidine,gelatin, cellulose, cellulose derivatives or the like. In another soliddosage form, a powder, marume, solution or suspension (e.g., inpropylene carbonate, vegetable oils or triglycerides) is encapsulated ina gelatin capsule.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc. an active compound as definedabove and optional pharmaceutical adjuvants in a carrier (e.g., water,saline, aqueous dextrose, glycerol, glycols, ethanol or the like) toform a solution or suspension. Injectables can be prepared inconventional forms, either as liquid solutions or suspensions, asemulsions, or in solid forms suitable for dissolution or suspension inliquid prior to injection. The percentage of active compound containedin such parenteral compositions is highly dependent on the specificnature thereof, as well as the activity of the compound and the needs ofthe subject. However, percentages of active ingredient of 0.01% to 10%in solution are employable, and will be higher if the composition is asolid that will be subsequently diluted to the above percentages.Preferably the composition will comprise 0.2-2% of the active agent insolution.

Formulations of the active compound or a salt may also be administeredto the respiratory tract as an aerosol or solution for a nebulizer, oras a microfine powder for insufflation, alone or in combination with aninert carrier such as lactose. In such a case, the particles of theformulation have diameters of less than 50 microns, preferably less than10 microns.

The present invention is more specifically illustrated by the followingexamples. However, it should be understood that these examples areprovided only for illustration of the present invention, but notintended to limit the present invention in any manner,

Materials

All culture media and fetal bovine serum (FBS) are purchased from LifeTechnologies (Grand Island, N.Y.).

EXAMPLE 1

Cell Culture

The Hep3B hepatoma was obtained from the American Type CultureCollection (Manassas, Va.). Hep3B cells were cultured in α-modifiedEagle's medium. All culture media were supplemented with 10%heat-inactivated FBS, 100 units/mL penicillin, and 100 μg/mLstreptomycin. All cells were grown in a humidified atmosphere containing5% CO₂ at 37° C., in which the oxygen tension in the incubator (VisionSci Co., model 9108MS2, Seoul, KOREA) was held at either 140 mm Hg (20%O₂, v/v, normoxic conditions) or 7 mm Hg (1% O₂, V/V, hypoxicconditions).

EXAMPLE 2

Effect of Compounds of Formula I or II on Hep3B Hepatoma Cell Xenografts

Male nude mice are injected subcutaneously in the flank with 5×10⁶viable Hep3B cells. After the tumors reached 100 to 150 mm³ in size,mice receive an intraperitoneal injection of a compound of Formula I orII (30 and 10 mg/kg) or vehicle (DMSO) daily for 2 weeks. After the lasttreatment, the mice are euthanized, the tumors removed and analyzed.

EXAMPLE 3

In Vitro Assays for HIF-1α and HIF-2α.

Hep3B hepatoma cells are cultured in α-modified Eagle's mediumsupplemented with 10% heat-activated fetal bovine serum, 100 units/mlpenicillin, and 100 μg/ml streptomycin in a humidified atmospherecontaining 5% CO₂ at 37° C. Oxygen tension in the incubator is held ateither 140 mm Hg (20% O₂, v/v, normoxia) or 7 mm Hg (1% O₂, v/v,hypoxia). After 24 hour stabilization under normoxic conditions, cellsare incubated under normoxic or hypoxic conditions for 18 hours in thepresence or in the absence of compounds of the invention. For theimmunoblotting of HIF-1α or HIF-2α in cultured cells, 20 μg of extractedproteins are separated on 6.5% SDS/polyacrylamide gels, and thentransferred to an Immobilon-P membrane (Millipore). Immobilized proteinsare incubated overnight at 4° C. with rat anti-HIF-1α(Chun et al., JCell Sci 2001 114:4051-4061) or anti-HIF-2α(Novus Biologicals,Littleton, Colo.), diluted 1:5000 in 5% nonfat milk in TBS/0.1% Tween-20(TTBS). Horseradish peroxidase-conjugated anti-rat antiserum is used asa secondary antibody and the complexes are visualized using an EnhancedChemiluminescence Plus Kit (Amersham Pharmacia Biotec). Among theanalogs with observed inhibition activity,{5-[1H-benzimidazol-1-yl]-furan-2-yl}-methanol and{5-[1-(prop-2-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol are stronginhibitors of HIF-1α and HIF-2α.

EXAMPLE 4

Effects on Angiogenesis, HIF-1α Protein, and VEGF Expression

To determine the mechanism by which the compounds of the inventioninhibit tumor growth, Hep3B tumors were examined morphologically andbiochemically. Male nude mice were injected subcutaneously in the flankwith 5×10⁶ viable Hep3B cells. After the tumors reached 100 to 150 mm³in size, mice received an intraperitoneal injection of the test compound(30 and 10 mg/kg) or vehicle (DMSO) daily for 2 weeks. After the lasttreatment, the mice were euthanized, the tumors, removed, fixed withformalin, and embedded in paraffin. Serial sections (6 μm thick) werecut from each paraffin block. One section was stained with hematoxylinand eosin (H&E) for histological assessment. Hematoxylin-eosin stainedtumor sections from vehicle-treated mice revealed well-developed bloodvessels containing red blood cells and frequent mitotic figures. Bycontrast, hematoxylin-eosin stained tumor sections treated mice tumorsrevealed frequent acinus formation without well-developed blood vessels.

To determine whether the inhibitory effect on tumor growth is associatedwith the suppression of tumor angiogenesis, we examined the distributionof the endothelial marker, CD31. Other sections were immunochemicallystained for HIF-1α a and the endothelial cell marker CD31. First, thesections were deparaffinized and rehydrated through a graded alcoholseries. Next, the sections were heated in 10 mM sodium citrate (pH 6.0)for 5 min in a microwave to retrieve the antigens. After blockingnonspecific sites with a blocking solution containing 2.5% BSA(SigmaAldrich Corp., St. Louis, Mo.) and 2% normal goat serum (LifeTechnologies) in a phosphate-buffered saline (pH 7.4) for 1 h, thesections were incubated overnight at 4° C. with rabbit polyclonalanti-CD31 (SantaCruz, 1:100 dilution in the blocking solution) or ratanti-HIF-1α (1:100 dilution in the blocking solution) antibodies, asdescribed previously (Kim et al., Circ Res 2002 90:E25-E33). Negativecontrol sections were incubated with diluent in the absence of anyprimary antibodies. The sections were then stained using standardmethods, and the avidin-biotin-horseradish peroxidase complex was usedto localize the bound antibodies, with diaminobenzidine as the finalchromogen. All immunostained sections were lightly counterstained withhematoxylin. Few CD31-immunopositive vessels were observed in tumorsections from drug-treated mice, whereas many vessels were observed intumor sections from vehicle-treated mice.

EXAMPLE 5 Preparation of [5-(benzimidazol-1-yl)-furan-2-yl]-methanol

Benzimidazole is mixed with 5-bromo-furan-2-yl formaldehyde in thepresence of CuI/N,N′-dimethylethylenediamine and cesium carbonate. Theresulting [5-(benzimidazol-1-yl)-furan-2-yl]-formaldehyde is purified,then reduced to the title compound with sodium borohydride.

EXAMPLE 6

The percentage of viable cells was measured by MTT assay. Cells wereplated in 12 well plates. After incubating cells for indicated time withDMSO or YC-1, MTT was add to media, final concentration of 0.5 mg/ml,and incubated for 3 h at 37° C. Resulting insoluble formazan wasdissolved with 0.04 N HCl in isopropanol. Absorbance of purple color offormazan was measured at 570 nm with a spectrophotometer. Cells wereincubated with 0.5, 1, or 2 μM YC-1 for 24, 48, or 72 h. Cell viabilitywas decreased by YC-1, dose-dependently and time-dependently (FIG. 2).

EXAMPLE 7

To test the effect of YC-1 on apoptosis, YC-1 (1 μM) was introduced to aculture of Hep3B and the caspase-3 activity was monitored for 72 h.Referring to FIG. 3 a, the caspase-3 activity increased over time toabout 5 times the activity in the control after 72 h. Caspase-3 is anenzyme that cleaves the 113 kDa protein poly-ADP-ribose-polymerase(PARP) to form an inactive 89 kDa fragment. Inactivation of PARP leadsto cell apoptosis. PARP protein was analyzed using Western blotting withanti-PARP antibody (BIOMOL Research Laboratories, Inc), diluted 1:5000.Referring to FIG. 3 b, the amount of the 89 kDa fragment of PARPincreased when the YC-1 dose was doubled, without apparent effect onactin production. For quantification of apoptosis at single cell level,based on labeling of DNA strand breaks, Terminal deoxynucleotidylTransferase-mediated dUTP Nick End Labeling (TUNEL) assay was performedaccording to the manufacturer's protocol (In Situ Cell Death DetectionKit; TMR Red; Roche Diagnostics GmbH, Mannheim, Germany). It is a methodfor detecting the 3′-OH ends of DNA exposed during the internucleosomalcleavage that occurs during apoptosis. Incorporation of fluorescein-dUTPallows detection by FACS. Cell were harvested, fixed directly with final2% PFA for 1 h at room temperature and permeabilized with 0.1% TritonX-100 in 0.1% sodium citrate for 5 min on ice. After labeling with TUNELreaction mixture with TdT for 1 h at 37° C., staining with propidiumiodide following FACS analysis. Referring to FIG. 3 c, the percentage ofTUNEL-positive cells increased dose-dependently. When caspase-3inhibitor was pre-treated before 1 h prior to treat YC-1, the percentageof TUNEL-positive cells decreased significantly.

EXAMPLE 8

Mesurement of HIF Proteins

To induce HIF-1α and HIF-2α proteins, Hep3B cells were incubated in ahypoxic chamber (1% oxygen tension) for 16 hours. YC-1 and relatedcompound at various concentations (0.3 to 10 μg/ml) were administeredinto the culture media just before hypoxic incubation. The amounts ofHIF proteins were measured by Western blotting method. Referring to FIG.4 a through FIG. 4 i, YC-1 and related compounds effectively reduced theexpressions of HIF proteins.

HIF Activity Assay

The synthetic DNA coding the HIF-binding enhancer region of the EPOgene, 5-GGTACCGGCCCTACGTGCTGTCTCACACAGCCTGTCTGACCTCTCGACCTACCGGCCAGATCT-3, was inserted into the pGL3 promoter plasmid (Promega). Toassay the HIF activity, Hep3B cells were cotransfected with theluciferase reporter gene and the plasmid cytomegalovirus-β-gal, usingthe calcium phosphate method. Transfected cells were split into ninealiquots and incubated for 42 h. After stabilizing, the cells wereincubated for 16 h at 20% or 1% O₂. They were then lysed and assayed forluciferase activity using a Biocounter M1500 luminometer (Lumac). β-galassays were performed for normalization of transfection. Referring toFIG. 4 a thrugh FIG. 4 i, YC-1 and related compounds effectively reducedHIF activity.

EXAMPLE 9 [5-(1-Methyl-1H-indazol-3-yl)-furan-2-yl]-methanol (CompoundA)

N-Methylfuranylindazole B was prepared from furanylindazole A andiodomethane in the presence of potassium t-butoxide at room temperature.Vilsmier-Haack reaction (POCl₃/DMF) of furanylindazole B gave thecorresponding aldehyde D which was then subjected to NaBH₄ reduction togive the title compound 2.

EXAMPLE 10[1-Benzyl-5-(1-methyl-1H-indazol-3-yl)-1H-pyrrol-2-yl]-methanol(Compound B)

EXAMPLE 11[1-Methyl-5-(1-methyl-1H-indazol-3-yl)-1H-pyrrol-2-yl]-methanol(Compound D)

Methylation of iodoindazole E (iodomethane/potassium t-butoxide) wasfollowed by Stille coupling of resulting N-methyliodoindazole F with tincompound G in the presence of catalytic Pd(0) to give the desired methylester H. Dibal reduction of methyl ester at 0° C. gave the titlecompound.

EXAMPLE 12[5-(1-Thiophen-2-yl-methyl-1H-indazole-3-yl)-furan-2-yl]-methanol(Compound C)

Reaction of furan-carboxaldehyde I with 2-bromomethylthiophene in thepresence of cesium carbonate as a base gave the desired product J andthe 2-position alkylated regio-isomer. The desired isomer J was purifiedby careful silica gel column chromatography and then subjected to aNaBH₄ reduction to give the title compound.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All patents and publications cited above are herebyincorporated by reference.

1. A method of inhibiting HIF expression in tumor cells or tissues in asubject, comprising administering to said subject a compositioncomprising a compound or mixture of compounds of the Formula I or II atan effective amount for inhibiting HIF expression:

wherein: X is N or CR; Y is N or C; R₁ is optionally substituted alkyl,optionally substituted aryl, or optionally substituted heterocyclyl; orR₁ is absent if Y is N; R₂ and R₃ are independently chosen from hydrogenor optionally substituted alkyl; or R₂ and R₃, together with the carbonsto which they are attached form an optionally substituted aromatic oroptionally substituted heteroaromatic ring; and R₄ is optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted alkyl; R₆ is hydrogen, optionally substituted aryl,optionally substituted heterocyclyl, or optionally substituted alkyl;including single isomers, mixtures of isomers, and pharmaceuticallyacceptable solvates and salts thereof; with the proviso that I is not3-(5′-hydroxymethyl-2′-furanyl)-1-benzylindazole;

wherein: A is —NH—R₅—(CO)—, —(CO)—R₅—NH— or naphthyl; and R₅ isoptionally substituted phenyl or optionally substituted pyridinyl.
 2. Amethod according to claim 1 wherein said effective amount is effectiveto inhibit HIF-1α expression.
 3. A method according to claim 1 whereinsaid effective amount is effective to inhibit HIF-2α expression.
 4. Amethod according to claim 1 wherein said tumor cells or tissue comprisetumors that overexpress HIF proteins.
 5. The method of claim 1, whereinsaid tumor is selected from the group consisting of hepatoma, stomachcarcinoma, renal carcinoma, cervical carcinoma and neuroblastoma, andprostate carcinoma.
 6. A method of inhibiting HIF-regulated geneexpression in tumor cells or tissues in a subject, comprisingadministering to said subject a composition comprising a compound ormixture of compounds of the Formula I or II at an effective amount forinhibiting HIF-regulated gene expression:

wherein: X is N or CR₆; Y is N or C; R₁ is optionally substituted alkyl,optionally substituted aryl, or optionally substituted heterocyclyl; orR₁ is absent if Y is N; R₂ and R₃ are independently chosen from hydrogenor optionally substituted alkyl; or R₂ and R₃, together with the carbonsto which they are attached form an optionally substituted aromatic oroptionally substituted heteroaromatic ring; and R₄ is optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted alkyl; R₆ is hydrogen, optionally substituted aryl,optionally substituted heterocyclyl, or optionally substituted alkyl;including single isomers, mixtures of isomers, and pharmaceuticallyacceptable solvates and salts thereof; with the proviso that I is not3-(5′-hydroxymethyl-2′-furanyl)-1-benzylindazole;

wherein: A is —NH—R₅—(CO)—, —(CO)—R₅—NH— or naphthyl; and R₅ isoptionally substituted phenyl or optionally substituted pyridinyl. 7.The method of claim 3 wherein said HIF-regulated gene is selected fromthe group consisting of erythropoietin, transferrin, transferrinreceptor, ceruloplasmin, vascular endothelial growth factor (VEGF), VEGFreceptor FLT-1, transforming growth factor β3, plasminogen activatorinhibitor 1, α1B adrenergic receptor, adrenomedullin, endothelin 1,nitric oxide synthase 2, heme oxygenase 1, glucose transporter 1 and 3,hexokinase 1 and 2, enolase 1, glyceraldehyde-3-phosphate dehydrogenase,phosphoglycerate kinase 1, phosphoglucokinase L, pyruvate kinase M,aldolase A and C, rios phosphate isomerase, lactate dehydrogenase A,carbonic anhydrase 9, adenylate kinase 3, propyl-4-hydroxylase al,insulin-like growth factor (IGF) 2, IGP-binding protein 1, 2 and 3, P21,Nip3, cyclin G2 and differentiated embryo chondrocyte
 1. 8. The methodof claim 4, wherein said HIF-regulated gene is selected from the groupconsisting of VEGF, aldolase A and enolase
 1. 9. A method according toclaim 6 wherein said effective amount is effective to inhibit HIF-1αexpression.
 10. A method according to claim 6 wherein said effectiveamount is effective to inhibit HIF-2α expression.
 11. A method accordingto claim 6 wherein said tumor cells or tissue comprise tumors thatoverexpress HIF proteins.
 12. The method of claim 6, wherein said tumoris selected from the group consisting of hepatoma, stomach carcinoma,renal carcinoma, cervical carcinoma, neuroblastoma, and prostatecarcinoma.
 13. A method of inhibiting angiogenesis in tumor cells ortissues in subject, comprising administering to said subject acomposition comprising a compound or mixture of compounds of the FormulaI or II at an effective amount for inhibiting angiogenesis:

wherein: X is N or CR₆; Y is N or C; R₁ is optionally substituted alkyl,optionally substituted aryl, or optionally substituted heterocyclyl; orR₁ is absent if Y is N; R₂ and R₃ are independently chosen from hydrogenor optionally substituted alkyl; or R₂ and R₃, together with the carbonsto which they are attached form an optionally substituted aromatic oroptionally substituted heteroaromatic ring; and R₄ is optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted alkyl; R₆ is hydrogen, optionally substituted aryl,optionally substituted heterocyclyl, or optionally substituted alkyl;including single isomers, mixtures of isomers, and pharmaceuticallyacceptable solvates and salts thereof; with the proviso that I is not3-(5′-hydroxymethyl-2′-furanyl)-1-benzylindazole;

wherein: A is —NH—R₅—(CO)—, —(CO)—R₅—NH— or naphthyl; and R₅ isoptionally substituted phenyl or optionally substituted pyridinyl.
 14. Amethod according to claim 13 wherein said tumor cells or tissue comprisetumors that overexpress HIF proteins.
 15. The method of claim 13,wherein said tumor is selected from the group consisting of hepatoma,stomach carcinoma, renal carcinoma, cervical carcinoma, neuroblastoma,and prostate carcinoma.
 16. A method of inhibiting tumor growth inanimal tissues in a subject, comprising administering to said subject acomposition comprising a compound or mixture of compounds of the FormulaI or II at an effective amount for inhibiting tumor growth:

wherein: X is N or CR₆; Y is N or C; R₁ is optionally substituted alkyl,optionally substituted aryl, or optionally substituted heterocyclyl; orR₁ is absent if Y is N; R₂ and R₃ are independently chosen from hydrogenor optionally substituted alkyl; or R₂ and R₃, together with the carbonsto which they are attached form an optionally substituted aromatic oroptionally substituted heteroaromatic ring; and R₄ is optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted alkyl; R₆ is hydrogen, optionally substituted aryl,optionally substituted heterocyclyl, or optionally substituted alkyl;including single isomers, mixtures of isomers, and pharmaceuticallyacceptable solvates and salts thereof; with the proviso that I is not3-(5′-hydroxymethyl-2′-furanyl)-1-benzylindazole;

wherein: A is —NH—R₅—(CO)—, —(CO)—R₅—NH— or naphthyl; and R₅ isoptionally substituted phenyl or optionally substituted pyridinyl.
 17. Amethod according to claim 16 wherein said tumor overexpresses HIFproteins.
 18. The method of claim 16, wherein said tumor is selectedfrom the group consisting of hepatoma, stomach carcinoma, renalcarcinoma, cervical carcinoma, neuroblastoma, and prostate carcinoma.19. A method of inhibiting tumor progression and metastasis in tissuesin a subject, comprising administering to said subject a compositioncomprising a compound or a mixture of compounds of the Formula I or IIat an effective amount for inhibiting tumor progression and metastasis:

wherein: X is N or CR₆; Y is N or C; R₁ is optionally substituted alkyl,optionally substituted aryl, or optionally substituted heterocyclyl; orR₁ is absent if Y is N; R₂ and R₃ are independently chosen from hydrogenor optionally substituted alkyl; or R₂ and R₃, together with the carbonsto which they are attached form an optionally substituted aromatic oroptionally substituted heteroaromatic ring; and R₄ is optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted alkyl; R₆ is hydrogen, optionally substituted aryl,optionally substituted heterocyclyl, or optionally substituted alkyl;including single isomers, mixtures of isomers, and pharmaceuticallyacceptable solvates and salts thereof; with the proviso that I is not3-(5′-hydroxymethyl-2′-furanyl)-1-benzylindazole;

wherein: A is —NH—R₅—(CO)—, —(CO)—R₅—NH— or naphthyl; and R₅ isoptionally substituted phenyl or optionally substituted pyridinyl.
 20. Amethod according to claim 1 wherein said tumor overexpresses HIFproteins.
 21. The method of claim 19, wherein said tumor is selectedfrom the group consisting of hepatoma, stomach carcinoma, renalcarcinoma, cervical carcinoma, neuroblastoma, and prostate carcinoma.22. A method of treating a HIF-mediated and/or VEGF-mediated disorder orcondition in a subject comprising administering to said subject acomposition comprising a therapeutically effective amount of a compoundor a mixture of compounds of the Formula I or II:

wherein: X is N or CR₆; Y is N or C; R₁ is optionally substituted alkyl,optionally substituted aryl, or optionally substituted heterocyclyl; orR₁ is absent if Y is N; R₂ and R₃ are independently chosen from hydrogenor optionally substituted alkyl; or R₂ and R₃, together with the carbonsto which they are attached form an optionally substituted aromatic oroptionally substituted heteroaromatic ring; and R₄ is optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted alkyl; R₆ is hydrogen, optionally substituted aryl,optionally substituted heterocyclyl, or optionally substituted alkyl;including single isomers, mixtures of isomers, and pharmaceuticallyacceptable solvates and salts thereof; with the proviso that I is not3-(5′-hydroxymethyl-2′-furanyl)-1-benzylindazole;

wherein: A is —NH—R₅—(CO)—, —(CO)—R₅—NH— or naphthyl; and R₅ isoptionally substituted phenyl or optionally substituted pyridinyl.
 23. Amethod according to claim 22 wherein overepression of HIF proteins is anindication of said disorders or condition.
 24. The method of claim 22,wherein said HIF-mediated disorder or condition is selected from thegroup consisting of hepatoma, stomach carcinoma, renal carcinoma,cervical carcinoma, neuroblastoma, and prostate carcinoma.
 25. Apharmaceutical composition comprising an amount effective of a compoundor mixture of compounds of the Formula I or II to arrest the cell cyclein proliferating cells in a subject; and a pharmaceutically acceptablecarrier:

wherein: X is N or CR₆; Y is N or C; R₁ is optionally substituted alkyl,optionally substituted aryl, or optionally substituted heterocyclyl; orR₁ is absent if Y is N; R₂ and R₃ are independently chosen from hydrogenor optionally substituted alkyl; or R₂ and R₃, together with the carbonsto which they are attached form an optionally substituted aromatic oroptionally substituted heteroaromatic ring; and R₄ is optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted alkyl; R₆ is hydrogen, optionally substituted aryl,optionally substituted heterocyclyl, or optionally substituted alkyl;including single isomers, mixtures of isomers, and pharmaceuticallyacceptable solvates and salts thereof;

wherein: A is —NH—R₅—(CO)—, —(CO)—R₅—NH— or naphthyl; and R₅ isoptionally substituted phenyl or optionally substituted pyridinyl.
 26. Amethod of enhancing the inhibitory effect on tumor growth in a subjectin combination with another antitumor therapy comprising administeringto said subject a composition comprising a compound or mixture ofcompounds of the Formula I or II at an effective amount forsynergistically enhancing the combined tumor-inhibiting effect of saidtherapy and said composition in said subject:

wherein: X is N or CR₆; Y is N or C; R₁ is optionally substituted alkyl,optionally substituted aryl, or optionally substituted heterocyclyl; orR₁ is absent if Y is N; R₂ and R₃ are independently chosen from hydrogenor optionally substituted alkyl; or R₂ and R₃, together with the carbonsto which they are attached form an optionally substituted aromatic oroptionally substituted heteroaromatic ring; and R₄ is optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted alkyl; R₆ is hydrogen, optionally substituted aryl,optionally substituted heterocyclyl, or optionally substituted alkyl;including single isomers, mixtures of isomers, and pharmaceuticallyacceptable solvates and salts thereof; with the proviso that I is not3-(5′-hydroxymethyl-2′-furanyl)-1-benzylindazole;

wherein: A is —NH—R₅—(CO)—, —(CO)—R₅—NH— or naphthyl; and R₅ isoptionally substituted phenyl or optionally substituted pyridinyl.
 27. Amethod for arresting the cell cycle in proliferating cells in a subjectcomprising administering to said subject a composition comprising acompound or mixture of compounds of the Formula I or II at an effectiveamount to inhibit progression of cell proliferation:

wherein: X is N or CR₆; Y is N or C; R₁ is optionally substituted alkyl,optionally substituted aryl, or optionally substituted heterocyclyl; orR₁ is absent if Y is N; R₂ and R₃ are independently chosen from hydrogenor optionally substituted alkyl; or R₂ and R₃, together with the carbonsto which they are attached form an optionally substituted aromatic oroptionally substituted heteroaromatic ring; and R₄ is optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted alkyl; R₆ is hydrogen, optionally substituted aryl,optionally substituted heterocyclyl, or optionally substituted alkyl;including single isomers, mixtures of isomers, and pharmaceuticallyacceptable solvates and salts thereof;

wherein: A is —NH—R₅—(CO)—, —(CO)—R₅—NH— or naphthyl; and R₅ isoptionally substituted phenyl or optionally substituted pyridinyl.
 28. Acompound of the Formula III

wherein X is N, or CR₆; Y is N or C; R₁ is optionally substitutedheterocyclyl, provided that when Y=N, and X=CH, R₁ is absent; R₄ is arylof 5 to 14 carbon atoms or alkyl of 1-10 carbon atoms; except that whenY=N and X=CH, R₄ may be optionally substituted heterocyclyl; R₆ ishydrogen, optionally substituted aryl, optionally substitutedheterocyclyl, or optionally substituted alkyl; and R₂ and R₃ areindependently hydrogen, optionally substituted alkyl, or R₂ and R₃together with the carbon atoms to which they are attached form anoptionally substituted aryl or optionally substituted heteroaryl ring.29. A compound according to claim 28 wherein X=N, Y=C and R₄ is alkyl of1-10 carbon atoms.
 30. A compound according to claim 29 wherein R₂ andR₃ together with the carbon atoms to which they are attached form anoptionally substituted aryl ring.
 31. A compound according to claim 30wherein R₄ is methyl.
 32. A compound according to claim 31 where R₁ is5-hydroxymethyl-furan-2-yl.
 33. A compound according to claim 31 whereinR₁ is N-methyl-5-hydroxymethyl-pyrrol-2-yl.
 34. A compound according toclaim 32 wherein R₂ and R₃ are joined to form a 6-membered aryl ring.35. A compound according to claim 33 wherein R₂ and R₃ are joined toform a 6-membered aryl ring.
 36. A compound according to claim 30wherein R₄ is ethyl.
 37. A compound according to claim 36 wherein R₁ is5-hydroxymethyl-furan-2-yl.
 38. A compound according to claim 37 whereinR₂ and R₃ are joined to form a 6-membered aryl ring.
 39. A compoundaccording to claim 30 wherein R₄ is i-propyl.
 40. A compound accordingto claim 39 wherein R₁ is 5-hydroxymethyl-furan-2-yl.
 41. A compoundaccording to claim 40 wherein R₂ and R₃ are joined to form a 6-memberedaryl ring.
 42. A compound according to claim 28 wherein X=N, Y=C and R₄is aryl of 5 to 14 carbon atoms.
 43. A compound according to claim 42wherein R₄ is phenyl.
 44. A compound according to claim 43 wherein R₁ isN-methyl-5-hydroxymethyl-pyrol-2-yl.
 45. A compound according to claim44 wherein R₂ and R₃ are joined to form a 6-membered aryl ring.
 46. Acompound according to claim 28 wherein X=CH and Y=N.
 47. A compoundaccording to claim 46 wherein R₄ is 5-hydroxymethyl-furan-2-yl.
 48. Acompound according to claim 47 wherein R₂ and R₃ are joined to form a6-membered aryl ring.
 49. The compound[5-(1-methyl-1H-indazol-3-yl)-furan-2-yl]-methanol according to claim34.
 50. The compound[1-methyl-5-(1-methyl-1H-indazol-3-yl)-1H-pyrrol-2-yl]-methanolaccording to claim
 35. 51. The compound[5-(1-ethyl-1H-indazol-3-yl)-furan-2-yl]-methanol according to claim 38.52. The compound [5-(1-(prop-2-yl)-1H-indazol-3-yl)-furan-2-yl]-methanolaccording to claim
 41. 53. The compound[N-methyl-5-(1-phenyl-1H-indazol-3-yl)-pyrrol-2-yl]-methanol accordingto claim
 45. 54. The compound[5-(1H-benzimidazol-1-yl)-furan-2-yl]-methanol according to claim 48.55. The compound[5-(1-benzyl-1H-indazol-3-yl)-1-methyl-1H-pyrrol-2-yl)-methanol.
 56. Thecompound[5-(1-thiophen-2-yl-methyl-1H-indazol-3-yl)-furan-2-yl]-methanol.
 57. Amethod according to claim 27 wherein said proliferating cells comprisetumors.
 58. A method according to claim 27 wherein said proliferatingcells comprise cells symptomatic of a hyper-proliferative skin disorder.59. A method according to any of claims 1 through 14, 16, 17, 47 or 48wherein said composition comprises a compound of the formula:

wherein X is N, or CR₆; Y is N or C; R₁ is optionally substitutedheterocyclyl, provided that when Y=N, and X=CH, R₁ is absent; R₄ is arylof 5 to 14 carbon atoms or alkyl of 1-10 carbon atoms; except that whenY=N and X=CH, R₄ may be optionally substituted heterocyclyl; R₆ ishydrogen, optionally substituted aryl, optionally substitutedheterocyclyl, or optionally substituted alkyl; and R₂ and R₃ areindependently hydrogen, optionally substituted alkyl, or R₂ and R₃together with the carbon atoms to which they are attached form anoptionally substituted aryl or optionally substituted heteroaryl ring.60. A method according to claim 59 wherein X=N, Y=C and R₄ is alkyl of1-10 carbon atoms.
 61. A method according to claim 60 wherein R₂ and R₃together with the carbon atoms to which they are attached form anoptionally substituted aryl ring.
 62. A method according to claim 61wherein R₄ is methyl.
 63. A method according to claim 62 where R₁ is5-hydroxymethyl-furan-2-yl.
 64. A method according to claim 62 whereinR₁ is N-methyl-5-hydroxymethyl-pyrrol-2-yl.
 65. A method according toclaim 63 wherein R₂ and R₃ are joined to form a 6-membered aryl ring.66. A method according to claim 64 wherein R₂ and R₃ are joined to forma 6-membered aryl ring.
 67. A method according to claim 61 wherein R₄ isethyl.
 68. A method according to claim 67 wherein R₁ is5-hydroxymethyl-furan-2-yl.
 69. A method according to claim 68 whereinR₂ and R₃ are joined to form a 6-membered aryl ring.
 70. A methodaccording to claim 61 wherein R₄ is i-propyl.
 71. A method according toclaim 70 wherein R₁ is 5-hydroxymethyl-furan-2-yl.
 72. A methodaccording to claim 63 wherein R₂ and R₃ are joined to form a 6-memberedaryl ring.
 73. A method according to claim 59 wherein X=N, Y=C and R₄ isaryl of 5 to 14 carbon atoms.
 74. A method according to claim 73 whereinR₄ is phenyl.
 75. A method according to claim 74 wherein R₁ isN-methyl-5-hydroxymethyl-pyrol-2-yl.
 76. A method according to claim 75wherein R₂ and R₃ are joined to form a 6-membered aryl ring.
 77. Amethod according to claim 59 wherein X=CH and Y=N.
 78. A methodaccording to claim 77 wherein R₄ is 5-hydroxymethyl-furan-2-yl.
 79. Amethod according to claim 78 wherein R₂ and R₃ are joined to form a6-membered aryl ring.
 80. A composition according to claim 25 comprisinga compound of the formula:

wherein X is N, or CR₆; Y is N or C; R₁ is optionally substitutedheterocyclyl, provided that when Y=N, and X=CH, R₁ is absent; R₄ is arylof 5 to 14 carbon atoms or alkyl of 1-10 carbon atoms; except that whenY=N and X=CH, R₄ may be optionally substituted heterocyclyl; R₆ ishydrogen, optionally substituted aryl, optionally substitutedheterocyclyl, or optionally substituted alkyl; and R₂ and R₃ areindependently hydrogen, optionally substituted alkyl, or R₂ and R₃together with the carbon atoms to which they are attached form anoptionally substituted aryl or optionally substituted heteroaryl ring.81. A method for preparing a compound of the formula VI comprising thesteps of (a) treating a compound of the formula IV with iron in aqueousacid to form a compound of the formula V;

(b) treating said compound of the formula V with NO₂ ⁻, then Sn⁺² toform a compound of the formula VI, wherein Ar is aryl or heteroaryl andR_(s) is H, optionally substituted alkyl, optionally substituted alkoxy,alkylenedioxy, optionally substituted, amino, optionally substitutedamidino, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aryloxy, optionally substituted araloxy, carboxy,carboalkoxy, carboxyalkyl, carboxamido, aminocarbonyl,benzyloxycarbonylamino, cyano, carbonyl, halogen, hydroxyl, optionallysubstituted heteroaryl, optionally substituted heteroaralkyl, optionallysubstituted heteroaryloxy, optionally substituted heteroaralalkoxy,nitro, sulfanyl, sulfinyl, sulfonyl or thio


82. A method according to claim 81 wherein Ar is heteroaryl.
 83. Amethod for preparing a compound of the formula IX comprising the stepsof (a) treating a compound of the formula VII with ArB(OH)₂ and Cu⁺² toform a compound of the formula VIII wherein Ar is aryl or heteroaryl:

(b) treating said compound of the formula VIII with R_(t)—Ar″—SnBu₃ inthe presence of palladium catalyst to produce a compound of the formulaIX wherein Ar″ is aryl or heteroaryl and R_(t) is H, optionallysubstituted alkyl, optionally substituted alkoxy, alkylenedioxy,optionally substituted, amino, optionally substituted amidino,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aryloxy, optionally substituted araloxy, carboxy,carboalkoxy, carboxyalkyl, carboxamido, aminocarbonyl,benzyloxycarbonylamino, cyano, carbonyl, halogen, hydroxyl, optionallysubstituted heteroaryl, optionally substituted heteroaralkyl, optionallysubstituted heteroaryloxy, optionally substituted heteroaralalkoxy,nitro, sulfanyl, sulfinyl, sulfonyl or thio.


84. A method according to claim 83 wherein Ar′ is aryl and Ar″ isheteroaryl.
 85. The compound [5-(1H-indazol-3-yl)-furan-2-yl]-methanol.86. The compound [5-(1-benzyl-1H-pyrazol-3-yl)-furan-2-yl]-methanol. 87.The compound 1-benzyl-3-furan-2-yl-1H-indazole.
 88. The compound1-benzyl-3-(5-methyl-furan-2-yl)-1H-indazole.
 89. The compound1-benzyl-3-(5-methoxymethyl-furan-2-yl)-1H-indazole.
 90. The compound2-[5-(1-benzyl-1H-indazol-3-yl)-furan-2-yl]-propan-2-ol.
 91. Thecompound 2-[5-(1-benzyl-1H-indazol-3-yl)-furan-2-ylmethoxy]-ethanol. 92.The compound 1-[5-(1-benzyl-1H-indazol-3-yl)-furan-2-yl]-ethanol. 93.The compound[5-(1-benzyl-1H-indazol-3-yl)-tetrahydro-furan-2-yl]-methanol.
 94. Thecompound C-[5-(1-benzyl-1H-indazol-3-yl)-furan-2-yl]-methylamine. 95.The compound [5-(1-benzyl-1H-indazol-3-yl)-furan-3-yl]-methanol.
 96. Thecompound [5-(1-benzyl-1H-indazol-3-yl)-thiophen-2-yl]-methanol.
 97. Thecompound[5-(1-benzyl-1H-indazol-3-yl)-1-methyl-1H-pyrrol-2-yl]-methanol.
 98. Thecompound [5-(1-benzyl-1H-indazol-3-yl)-1H-pyrrol-2-yl]-methanol.
 99. Thecompound [4-(1-benzyl-1H-indazol-3-yl)-phenyl]-methanol.
 100. Thecompound [6-(1-benzyl-1H-indazol-3-yl)-pyridin-3-yl]-methanol.
 101. Thecompound [5-(1-benzyl-1H-indazol-3-yl)-pyridin-2-yl]-methanol.
 102. Thecompound [3-(1-benzyl-1H-indazol-3-yl)-phenyl]-methanol.
 103. Thecompound [4-(1-benzyl-1H-indazol-3-yl)-pyridin-2-yl]-methanol.
 104. Thecompound [6-(1-benzyl-1H-indazol-3-yl)-pyridin-2-yl]-methanol.
 105. Thecompound [6-(1-benzyl-H-indazol-3-yl)-pyridin-2-yl]-methanol.
 106. Thecompound 4-[3-(5-hydroxymethyl-furan-2-yl)-indazol-1-ylmethyl]-phenol.107. The compound{5-[1-(4-amino-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 108. Thecompound {5-[1-(4-fluoro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.109. The compound{5-[1-(4-nitro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 110. Thecompound{5-[1-(4-trifluoromethyl-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.111. The compound{5-[1-(4-methoxy-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 112. Thecompound {5-[1-(4-chloro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.113. The compound{5-[1-(4-cyano-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 114. Thecompound {5-[1-(3-amino-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.115. The compound{5-[1-(3-fluoro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 116. Thecompound {5-[1-(3-nitro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.117. The compound{5-[1-(3-trifluoromethyl-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.118. The compound{5-[1-(3-methoxy-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 119. Thecompound {5-[1-(3-chloro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.120. The compound{5-[1-(3-cyano-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 121. Thecompound {5-[1-(3-methyl-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.122. The compound{5-[1-(2-amino-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 123. Thecompound {5-[1-(2-fluoro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.124. The compound{5-[1-(2-nitro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 125. Thecompound{5-[1-(2-trifluoromethyl-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.126. The compound{5-[1-(2-methoxy-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 127. Thecompound {5-[1-(2-chloro-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.128. The compound{5-[1-(2-cyano-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 129. Thecompound {5-[1-(2-methyl-benzyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.130. The compound3-[3-(5-hydroxymethyl-furan-2-yl)-indazol-1-ylmethyl]-phenol.
 131. Thecompound 2-[3-(5-hydroxymethyl-furan-2-yl)-indazol-1-ylmethyl]-phenol.132. The compound[5-(1-pyridin-2-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol.
 133. Thecompound [5-(1-pyridin-3-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol.134. The compound[5-(1-pyridin-4-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol.
 135. Thecompound [5-(1-cyclohexylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol.136. The compound[5-(1-furan-3-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol.
 137. Thecompound[5-(1-thiophen-3-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol. 138.The compound{5-[1-(1-methyl-1H-pyrrol-3-ylmethyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.139. The compound{5-[1-(1H-pyrrol-3-ylmethyl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 140.The compound[5-(1-furan-2-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol.
 141. Thecompound[5-(1-thiophen-2-ylmethyl-1H-indazol-3-yl)-furan-2-yl]-methanol. 142.The compound{5-[1-(1-methyl-1H-pyrrol-2-ylmethyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.143. The compound{5-[1-(1H-pyrrol-2-ylmethyl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 144.The compound [5-(1-phenethyl-1H-indazol-3-yl)-furan-2-yl]-methanol. 145.The compound[5-(1-benzyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-furan-2-yl]-methanol. 146.The compound [5-(1-phenyl-1H-indazol-3-yl)-furan-2-yl]-methanol. 147.The compound[5-(1-benzyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-furan-2-yl]-methanol. 148.The compound[5-(1-benzyl-5-methyl-1H-indazol-3-yl)-furan-2-yl]-methanol.
 149. Thecompound[5-(1-benzyl-5-trifluoromethyl-1H-indazol-3-yl)-furan-2-yl]-methanol.150. The compound[5-(1-benzyl-5-hydroxy-1H-indazol-3-yl)-furan-2-yl]-methanol.
 151. Thecompound [5-(1-benzyl-5-amino-1H-indazol-3-yl)-furan-2-yl]-methanol.152. The compound[5-(1-benzyl-5-fluoro-1H-indazol-3-yl)-furan-2-yl]-methanol.
 153. Thecompound [5-(1-benzyl-5-methoxy-1H-indazol-3-yl)-furan-2-yl]-methanol.154. The compound[5-(1-benzyl-5-nitro-1H-indazol-3-yl)-furan-2-yl]-methanol.
 155. Thecompound [5-(1-benzyl-5-cyano-1H-indazol-3-yl)-furan-2-yl]-methanol.156. The compound[5-(1-benzyl-5-chloro-1H-indazol-3-yl)-furan-2-yl]-methanol.
 157. Thecompound [5-(1-benzyl-6-methyl-1H-indazol-3-yl)-furan-2-yl]-methanol.158. The compound[5-(1-benzyl-6-trifluoromethyl-1H-indazol-3-yl)-furan-2-yl]-methanol.159. The compound[5-(1-benzyl-6-hydroxy-1H-indazol-3-yl)-furan-2-yl]-methanol.
 160. Thecompound [5-(1-benzyl-6-amino-1H-indazol-3-yl)-furan-2-yl]-methanol.161. The compound[5-(1-benzyl-6-fluoro-1H-indazol-3-yl)-furan-2-yl]-methanol.
 162. Thecompound [5-(1-benzyl-6-methoxy-1H-indazol-3-yl)-furan-2-yl]-methanol;163. The compound[5-(1-benzyl-6-nitro-1H-indazol-3-yl)-furan-2-yl]-methanol.
 164. Thecompound [5-(1-benzyl-6-cyano-1H-indazol-3-yl)-furan-2-yl]-methanol.165. The compound[5-(1-benzyl-6-chloro-1H-indazol-3-yl)-furan-2-yl]-methanol.
 166. Thecompound {5-[(3-benzyl)-1H-indazol-3-yl-]-furan-2-yl}-methanol.
 167. Thecompound (2′-hydroxymethyl)-(2-benzyl)-1H-indazol [6,7:5′,4′]furan. 168.The compound {5-[(7-phenyl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 169.The compound {5-[1-methyl-1H-benzimidazol-4-yl]-furan-2-yl}-methanol.170. The compound{5-[1-(2-methyl-prop-2-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 171.The compound{5-[(1-(furan-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 172.The compound{5-[(1-(thien-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 173.The compound{5-[(1-(N-methyl-pyrrol-2′yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.174. The compound{5-[(1-(furan-3′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl]furan-2-yl}-methanol.175. The compound{5-[(1-(thien-3′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 176.The compound{5-[(1-(N-methyl-pyrrol-3′yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.177. The compound{5-[(1-(oxa-3′,4′-diazol-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.178. The compound{5-[(1-(pyrrol-1′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.179. The compound{5-[(1-(thia-3′,4′-diazol-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.180. The compound{5-[(1-(4′-methyl-1′,2′,4′-triazol-5′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.181. The compound{5-[(1-(1′,2′,4′-triazol-1′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.182. The compound{5-[(1-(1′,2′,4′-triazol-4′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.183. The compound{5-[(1-(1′,3′-oxazol-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.184. The compound{5-[(1-(1′,3′-thiazol-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.185. The compound{5-[(1-(1′-methyl-1′,3′-diazol-2′-yl)-1H-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.186. The compound{5-[(1-(1′,3′-oxazol-5′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.187. The compound{5-[(1-(1′,3′-thiazol-5′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.188. The compound{5-[(1-(1′-methyl-1′3′-diazol-5′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.189. The compound{5-[(1-(1′,3′-oxazol-4′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.190. The compound{5-[(1-(1′,3′-thiazol-4′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.191. The compound{5-[(1-(1′-methyl-1′,2′-diazol-5′-yl)-methyl)-1H1H-indazol-3-yl]-furan-2-yl}-methanol.192. The compound{5-[(1-(1′-methyl-1′,3′-diazol-4′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.193. The compound{5-[(1-(1′,3′-diazol-1′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.194. The compound{5-[(1-(1′-methyl-1′,2′-diazol-4′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.195. The compound{5-[(1-(1′-methyl-1′,2′-diazol-3′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.196. The compound{5-[(1-(1′,2′-diazol-1′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.197. The compound{5-[(1-(furan-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 198.The compound{5-[(1-(thien-2′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 199.The compound{5-[(1-(N-methyl-pyrrol-2′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.200. The compound{5-[(1-(pyrrol-1′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol.201. The compound{5-[(1-(furan-3′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 202. Thecompound{5-[(1-(thien-3′-yl)-methyl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 203.The compound{5-[(1-(N-methyl-pyrrol-3′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.204. The compound {5-[(1-(4′-methyl-1′, 2′,4′-triazol-5′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 205. Thecompound {5-[(1-(1′, 2′,4′-triazol-4′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 206. Thecompound{5-[(1-(thia-3′-4′diazol-2′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.207. The compound{5-[(1-(1′,3′-oxazol-2′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 208.The compound{5-[(1-(1′,3′-thiazol-2′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 209.The compound{5-[(1-(1′-methyl-1′,3′-diazol-2′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.210. The compound{5-[(1-(1′,3′-oxazol-4′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 211.The compound{5-[(1-(1′,3′-thiazol-4′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 212.The compound{5-[(1-(1′-methyl-1,3′-diazol)-4′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.213. The compound {5-[(1-(1′,3-diazol-1′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 214. The compound{5-[(1-(1′,3′-oxazol-5′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 215.The compound {5-[(1-(1′,3′,-thiazol-5′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.
 216. Thecompound{5-[(1-(1′-methyl-1′,3′-diazol-5′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.217. The compound{5-[(1-(1′-methyl-1′,2′-diazol-5′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.218. The compound{5-[(1-(1′,2′-diazol-1′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol. 219.The compound{5-[(1-(1′-methyl-1′,2′-diazol-3′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.220. The compound{5-[(1-(1′-methyl-1′,2′-diazol-4′-yl)-1H-indazol-3-yl]-furan-2-yl}-methanol.221. The compound {5-[1-benzyl-1H-indazol-3-yl]-furan-3-yl}-methanol.222. The compound {5-[1-benzyl-1H-indazol-3-yl]-thien-3-yl}-methanol.223. The compound{N-methyl-5-[benzyl-1H-indazol-3-yl]-pyrrol-3-yl}-methanol.
 224. Thecompound {4-[1-benzyl-1H-indazol-3-yl]-furan-2-yl}-methanol.
 225. Thecompound {4-[1-benzyl-1H-indazol-3-yl]-thien-2-yl}-methanol.
 226. Thecompound {N-methyl-4-[1-benzyl-1H-indazol-3-yl]-pyrrol-2-yl}-methanol.227. The compound{4-methyl-5-[1-benzyl-1H-indazol-3-yl]-1,2,4-triazol-3-yl}-methanol.228. The compound {5-[1-benzyl-1H-indazol-3-yl]-thien-2-yl}-methanol.229. The compound{1-[1-benzyl-1H-indazol-3-yl]-1,2,4-triazol-3-yl}-methanol.
 230. Thecompound {1-[1-benzyl-1H-indazol-3-yl]-pyrrol-3-yl}-methanol.
 231. Thecompound {5-[1-benzyl-1H-indazol-3-yl]-oxa-3-4-diazol-2-yl}-methanol.232. The compound{5-[1-benzyl-1H-indazol-3-yl]-thia-3,4-diazol-2-yl}-methanol.
 233. Thecompound {1-[1-benzyl-1H-indazol-3-yl]-1,2-diazol-4-yl}-methanol. 234.The compound {1-[1-benzyl-1H-indazol-3-yl]-1,2-diazol-3-yl}-methanol.235. The compound{1-methyl-3-[1-benzyl-1H-indazol-3-yl]-1,2-diazol-5-yl}-methanol. 236.The compound{1-methyl-5-[1-benzyl-1H-indazol-3-yl]-1,2-diazol-3-yl}-methanol. 237.The compound {1-[1-benzyl-1H-indazol-3-yl]-1,3-diazol-4-yl}-methanol.238. The compound{2-[1-benzyl-1H-indazol-3-yl]-1,3-oxazol-5-yl}-methanol.
 239. Thecompound {2-[1-benzyl-1H-indazol-3-yl]-1,3-thiazol-5-yl}-methanol. 240.The compound{1-methyl-2-[1-benzyl-1H-indazol-3-yl]-1,3-diazol-5-yl}-methanol. 241.The compound {5-[1-benzyl-1H-indazol-3-yl]-1,3-oxazol-5-yl}-methanol.242. The compound{2-[1-benzyl-1H-indazol-3-yl]-1,3-oxazol-4-yl}-methanol.
 243. Thecompound {2-[1-benzyl-1H-indazol-3-yl]-1,3-thiazol-4-yl}-methanol. 244.The compound{1-methyl-2-[1-benzyl-1H-indazol-3-yl]-1,3-diazol-4-yl}-methanol. 245.The compound{1-methyl-5-[1-benzyl-1H-indazol-3-yl]-1,3-diazol-2-yl}-methanol. 246.The compound {4-[1-benzyl-1H-indazol-3-yl]-1,3-oxazol-2-yl}-methanol.247. The compound{4-[1-benzyl-1H-indazol-3-yl]-1,3-thiazol-2-yl}-methanol.
 248. Thecompound{1-methyl-4-[1-benzyl-1H-indazol-3-yl]-1,3-diazol-2-yl}-methanol. 249.The compound {5-[1-benzyl-1H-indazol-3-yl]-1,3-thiazol-2-yl}-methanol.250. The compound{2-[1-phenyl-1H-indazol-3-yl]-1,3-oxazol-5-yl}-methanol.
 251. Thecompound {2-[1-phenyl-1H-indazol-3-yl]-1,3-thiazol-5-yl}-methanol. 252.The compound{1-methyl-2-[1-phenyl-1H-indazol-3-yl]-1,3-diazol-5-yl}-methanol. 253.The compound {2-[1-phenyl-1H-indazol-3-yl]-1,3-oxazol-4-yl}-methanol.254. The compound{2-[1-phenyl-1H-indazol-3-yl]-1,3-thiazol-4-yl}-methanol.
 255. Thecompound{1-methyl-2-[1-phenyl-1H-indazol-3-yl]-1,3-diazol-4-yl}-methanol. 256.The compound {1-[1-phenyl-1H-indazol-3-yl]-1,3-diazol-4-yl}-methanol.257. The compound{4-[1-phenyl-1H-indazol-3-yl]-1,3-oxazol-2-yl}-methanol.
 258. Thecompound {4-[1-phenyl-1H-indazol-3-yl]-1,3-thiazol-2-yl}-methanol. 259.The compound{1-methyl-4-[1-phenyl-1H-indazol-3-yl]-1,3-diazol-2-yl}-methanol. 260.The compound {5-[1-phenyl-1H-indazol-3-yl]-1,3-oxazol-2-yl}-methanol.261. The compound{5-[1-phenyl-1H-indazol-3-yl]-1,3-thiazol-2-yl}-methanol.
 262. Thecompound{1-methyl-5-[1-phenyl-1H-indazol-3-yl]-1,3-diazol-2-yl}-methanol. 263.The compound {5-[1-phenyl-1H-indazol-3-yl]-furan-3-yl}-methanol. 264.The compound {5-[1-phenyl-1H-indazol-3-yl]-thien-3-yl}-methanol. 265.The compound{N-methyl-5-[1-phenyl-1H-indazol-3-yl]-pyrrol-3-yl}-methanol.
 266. Thecompound {4-[1-phenyl-1H-indazol-3-yl]-furan-2-yl}-methanol.
 267. Thecompound {4-[1-phenyl-1H-indazol-3-yl]-thien-2-yl}-methanol.
 268. Thecompound {N-methyl-4-[1-phenyl-1H-indazol-3-yl]-pyrrol-2-yl}-methanol.269. The compound {5-[1-phenyl-1H-indazol-3-yl]-furan-2-yl}-methanol.270. The compound {5-[1-phenyl-1H-indazol-3-yl]-thien-2-yl}-methanol.271. The compound{4-methyl-5-[1-phenyl-1H-indazol-3-yl]-1,2,4-triazol-3-yl}-methanol.272. The compound{1-[1-phenyl-1H-indazol-3-yl]-1,2,4-triazol-3-yl}-methanol.
 273. Thecompound {N-[1-phenyl-1H-indazol-3-yl]-pyrrol-3-yl}-methanol.
 274. Thecompound {5-[1-phenyl-1H-indazol-3-yl]-oxadiazol-2-yl}-methanol. 275.The compound {5-[1-phenyl-1H-indazol-3-yl]-thiadiazol-2-yl}-methanol.276. The compound{2-methyl-5-[1-phenyl-1H-indazol-3-yl]-1,2-diazol-3-yl}-methanol. 277.The compound{1-methyl-3-[1-phenyl-1H-indazol-3-yl]-1,2-diazol-5-yl}-methanol. 278.The compound {1-[1-phenyl-1H-indazol-3-yl]-1,2-diazol-4-yl}-methanol.279. The compound{1-[1-phenyl-1H-indazol-3-yl]-1,2-diazol-3-yl}-methanol.
 280. Thecompound {5-[4-phenyl-1H-benzimidazol-1-yl]-furan-2-yl}-methanol. 281.The compound {N-methyl-5-[1H-benzimidazol-1-yl]-pyrrol-2-yl}-methanol.282. The compound{1-methyl-2-[1H-benzimidazol-1-yl]-1,3-diazol-5-yl}-methanol.
 283. Thecompound {3-[1H-benzimidazol-1-yl]-benzyl alcohol.
 284. The compound{N-methyl-5-[1H-benzimidazol-1-yl-methyl]-pyrrol-2-yl}}-methanol. 285.The compound (3-(1H-benzo[d]imidazol-1-yl)phenyl)-methanol.
 286. Thecompound 2-(3-(5-(hydroxymethyl)furan-2-yl)-1H-indazol-1-yl)-aceticacid.
 287. The compound2-(3-(5-(hydroxymethyl)-furan-2-yl)-1H-indazol-1-yl)-ethanol.
 288. Thecompound 2-((5-(1-methyl-1H-indazol-3-yl)-furan-2-yl)methoxy)-ethanol.289. The compound{N-methyl-5-[1-thiophen-2-yl-methyl-1H-indazol-3-yl]-pyrrol-2-yl}-methanol.